TW202241862A

TW202241862A - Dimethylamide compounds, their preparation methods and medical use

Info

Publication number: TW202241862A
Application number: TW111104075A
Authority: TW
Inventors: 楊方龍; 楊倩; 賀峰; 陶維康
Original assignee: 大陸商江蘇恆瑞醫藥股份有限公司; 大陸商上海恆瑞醫藥有限公司
Priority date: 2021-02-01
Filing date: 2022-01-28
Publication date: 2022-11-01
Also published as: CN116783166A; WO2022161447A1

Abstract

The present disclosure relates to dimethylamide compounds, their preparation methods and medical use. Specifically, the present disclosure relates to a dimethylamide compound represented by the general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound, and its use as a therapeutic agent, especially its use in the preparation of medicaments for inhibiting protein kinases. Wherein, each group in the general formula (I) is as defined in the specification.

Description

二甲醯胺類化合物、其製備方法及其在醫藥上的應用 Diformamide compound, its preparation method and its application in medicine

本揭露屬於醫藥領域，關於一種二甲醯胺類化合物、其製備方法及其在醫藥上的應用。特別地，本揭露關於通式(I)所示的二甲醯胺類化合物、其製備方法及含有該類化合物的醫藥組成物，以及其在製備用於抑制蛋白激酶的藥物中的用途。 The disclosure belongs to the field of medicine, and relates to a dimethylamide compound, its preparation method and its application in medicine. In particular, the disclosure relates to dimethylamide compounds represented by general formula (I), their preparation methods, pharmaceutical compositions containing such compounds, and their use in the preparation of drugs for inhibiting protein kinases.

受體酪胺酸激酶(RTKs)屬於細胞膜表面的跨膜蛋白家族，其主要功能是將細胞外信號傳導至細胞內並參與調控生存、生長、增殖、分化、黏附和遷移等一系列過程。 Receptor tyrosine kinases (RTKs) belong to the family of transmembrane proteins on the surface of cell membranes. Their main function is to transduce extracellular signals into cells and participate in the regulation of a series of processes such as survival, growth, proliferation, differentiation, adhesion and migration.

VEGF/VEGFR信號傳導是血管生成的主要限速步驟，病理性血管生成是腫瘤發生的標誌，原發性腫瘤的生長及其隨後的轉移取決於血管生成，在大多數實體瘤中均發現VEGF/VEGFR的高表達； VEGF/VEGFR signaling is the major rate-limiting step in angiogenesis Pathological angiogenesis is a hallmark of tumorigenesis Primary tumor growth and its subsequent metastasis depend on angiogenesis VEGF/VEGFR is found in most solid tumors High expression of VEGFR;

VEGF/VEGFR抑制劑治療限制：藉由臨床和臨床前的數據來看，單純抑制VEGFR表達的治療方法存在一定的局限性，例如單藥治療雖然可以延遲腫瘤的生長，但大多數不會導致腫瘤消退，並且可能誘發癌症的侵襲性或轉移性行為，使用貝伐珠單抗(bevacizumab)進行單藥治療，雖然可以提高腫瘤患者的PFS，但無法有效增加患者的總生存期。而且VEGF/VEGFR療法存在原發和繼發耐藥，後者通常是由於其他重要基因/蛋白被上調造成的，如在VEGFR靶點治療後的腎癌患者中，發現MET和Axl的高表達促進了腫瘤發展。因此VEGF/VEGFR療法通常需要與其他藥物聯用。 VEGF/VEGFR inhibitor treatment limitations: According to clinical and preclinical data, there are certain limitations in the treatment of simply inhibiting the expression of VEGFR. For example, although monotherapy can delay tumor growth, most of them will not cause tumor growth. Regression, and may induce aggressive or metastatic behavior of the cancer, monotherapy with bevacizumab, Although it can improve the PFS of tumor patients, it cannot effectively increase the overall survival of patients. Moreover, VEGF/VEGFR therapy has primary and secondary drug resistance, and the latter is usually caused by the upregulation of other important genes/proteins. For example, in patients with kidney cancer after VEGFR target therapy, it was found that the high expression of MET and Axl promoted tumor development. Therefore, VEGF/VEGFR therapy usually needs to be used in combination with other drugs.

TAM亞家族是由TYRO3、Axl和Mer三種酪胺酸激酶組成。TAM家族激酶的胞外配體結合域由兩個免疫球蛋白樣結構域及兩個纖黏蛋白III結構域組成。目前已經確認TAM的天然配體分別為生長阻滯特異性蛋白6(GAS6)和蛋白S(PROS1)。GAS6能結合並激活全部三種TAM激酶，PROS1則是Mer和TYRO3兩種激酶的配體。 The TAM subfamily consists of three tyrosine kinases, TYRO3, Axl and Mer. The extracellular ligand-binding domain of TAM family kinases consists of two immunoglobulin-like domains and two fibronectin III domains. It has been confirmed that the natural ligands of TAM are growth arrest specific protein 6 (GAS6) and protein S (PROS1). GAS6 binds and activates all three TAM kinases, and PROS1 is a ligand for both Mer and TYRO3 kinases.

Axl(也被稱為UFO、ARK、JTK11和TYRO7)最早在慢性髓性白血病人的DNA中作為轉化基因被發現。GAS6結合Axl之後可以誘導其自磷酸化並激活酪胺酸激酶Axl。Axl能繼續活化下游多個信號傳導途徑中的蛋白包括PI3K-AKT，Raf-MAPK，PLC-PKC等。 Axl (also known as UFO, ARK, JTK11 and TYRO7) was first identified as a transforming gene in the DNA of patients with chronic myeloid leukemia. Binding of GAS6 to Axl can induce its autophosphorylation and activate the tyrosine kinase Axl. Axl can continue to activate proteins in multiple downstream signaling pathways, including PI3K-AKT, Raf-MAPK, PLC-PKC and so on.

Mer(也被稱為MERTK、EYK、RYK、RP38、NYK和TYRO12)最早作為磷蛋白在類淋巴母細胞表達文庫中被發現。GAS6和PROS1均能夠與Mer結合並誘導其發生磷酸化並活化Mer激酶。與Axl類似，Mer活化之後也能將信號向下游繼續傳導，比如活化PI3K-AKT和Raf-MAPK通路。 Mer (also known as MERTK, EYK, RYK, RP38, NYK, and TYRO12) was first discovered as a phosphoprotein in a lymphoblastoid expression library. Both GAS6 and PROS1 can bind to Mer and induce its phosphorylation and activation of Mer kinase. Similar to Axl, after Mer activation, the signal can also be transmitted downstream, such as the activation of PI3K-AKT and Raf-MAPK pathways.

TYRO3(也被稱為DTK、SKY、RSE、BRT、TIF和ETK2)最早由基於PCR技術的選殖研究中發現。GAS6和PROS1均能夠與TYRO3結合並激活該激酶。儘管TYRO3活化的下游信號通路在TAM家族中研究的最少，目前的結果顯示似乎PI3K-AKT和Raf-MAPK通路被TYRO3所激活。TYRO3、Axl和Mer在腫瘤中均被發現過表達。 TYRO3 (also known as DTK, SKY, RSE, BRT, TIF, and ETK2) was first discovered in colonization studies based on PCR technology. Both GAS6 and PROS1 are able to bind to TYRO3 and activate this kinase. Although the downstream signaling pathways activated by TYRO3 are in TAM home The least studied in the family, the current results show that the PI3K-AKT and Raf-MAPK pathways seem to be activated by TYRO3. TYRO3, Axl and Mer were all found to be overexpressed in tumors.

MET家族包括了間葉-上皮轉化因子(c-Met)，一種獨立的表達於多種上皮細胞表面的酪胺酸激酶受體；它的天然配體為肝細胞生長因子/分散因子(HGF/SF)。天然配體HGF結合於c-Met後會開啟一系列細胞內的信號傳導過程，包括正常細胞的胚胎發育和傷口癒合。然而，在腫瘤細胞中，由於c-Met基因突變、過表達和擴增，引起了HGF/c-Met軸異常活化並激活PI3K/AKT、Ras/MAPK、JAK/STAT、SRC和Wnt/β-連環素信號通路使得腫瘤生長增殖。由於持續活化上述提到的c-Met依賴性信號傳導通路使得腫瘤細胞獲得了相比正常細胞更多的競爭優勢，並且藉由接觸血液供給和增加脫離組織的能力使得腫瘤發生轉移的可能性大大增加。 The MET family includes mesenchymal-epithelial transition factor (c-Met), an independent tyrosine kinase receptor expressed on the surface of various epithelial cells; its natural ligand is hepatocyte growth factor/scatter factor (HGF/SF ). After the natural ligand HGF binds to c-Met, it will start a series of intracellular signal transduction processes, including embryonic development of normal cells and wound healing. However, in tumor cells, due to the mutation, overexpression and amplification of c-Met gene, the HGF/c-Met axis is abnormally activated and activates PI3K/AKT, Ras/MAPK, JAK/STAT, SRC and Wnt/β- The catenin signaling pathway enables tumor growth and proliferation. Due to the continuous activation of the c-Met-dependent signaling pathway mentioned above, tumor cells gain more competitive advantages than normal cells, and the possibility of tumor metastasis is greatly increased by contacting blood supply and increasing the ability to detach from tissues. Increase.

目前已公開的專利申請有WO2005030140A2、WO2010045095A1、WO2010075376A2、WO2019148044A1、CN102212062A和WO2012006960A1等，這些專利申請中的活性都還有提升空間，相關病患人群中存在重大未滿足的醫學需求。 Currently published patent applications include WO2005030140A2, WO2010045095A1, WO2010075376A2, WO2019148044A1, CN102212062A and WO2012006960A1, etc. There is still room for improvement in the activities of these patent applications, and there are major unmet medical needs in the relevant patient population.

因此，為治療KDR(VEGFR2)、TAM和MET激酶介導的腫瘤需要開發一類新的化合物來更好的調控這類靶點。 Therefore, for the treatment of tumors mediated by KDR (VEGFR2), TAM and MET kinases, it is necessary to develop a new class of compounds to better regulate these targets.

本揭露的目的在於提供一種通式(I)所示的化合物或其可藥用的鹽： The purpose of this disclosure is to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:

其中， in,

環A選自6至10員芳基、5至10員雜芳基、3至8員環烷基和3至8員雜環基； Ring A is selected from 6 to 10 membered aryl, 5 to 10 membered heteroaryl, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclyl;

G₁為N原子或CR^2a； G ₁ is N atom or CR ^2a ;

G₂為N原子或CR^2b； G ₂ is N atom or CR ^2b ;

G₃為N原子或CR^3a； G ₃ is N atom or CR ^3a ;

各個R¹相同或不同，且各自獨立地選自氫原子、鹵素、烷基、烷氧基、鹵烷基、鹵烷氧基、氰基、胺基、硝基、羥基、羥烷基、環烷基、雜環基、芳基和雜芳基；其中該烷基、烷氧基、環烷基、雜環基、芳基和雜芳基各自獨立地視需要被選自鹵素、烷基、烷氧基、鹵烷基、鹵烷氧基、氰基、胺基、硝基、羥基、羥烷基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所取代； Each R is the same or different, and each independently selected from ^a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amine, nitro, hydroxyl, hydroxyalkyl, ring Alkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from the group consisting of halogen, alkyl, One or more substituents of alkoxy, haloalkyl, haloalkoxy, cyano, amine, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl replaced by

R²、R^2a和R^2b相同或不同，且各自獨立地選自氫原子、鹵素、烷基、烷氧基、鹵烷基、鹵烷氧基、氰基、胺基、硝基、羥基、羥烷基、環烷基和雜環基； R ² , R ^2a and R ^2b are the same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, Hydroxyalkyl, cycloalkyl and heterocyclyl;

R³和R^3a相同或不同，且各自獨立地選自氫原子、鹵素、烷基、烷氧基、鹵烷基、鹵烷氧基、氰基、胺基、硝基、羥基、羥烷基、環烷基和雜環基； R ³ and R ^3a are the same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl , cycloalkyl and heterocyclyl;

R⁴選自氫原子、烷基、鹵烷基、羥烷基、環烷基和雜環基； R ^is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group;

R⁵選自烷基、-(CH₂)_mR^a、環烷基和雜環基；其中該烷基、環烷基和雜環基各自獨立地視需要被選自鹵素、烷基、烷氧基、鹵烷基、鹵烷氧基、氰基、胺基、硝基、羥基、羥烷基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所取代； R ⁵ is selected from alkyl, -(CH ₂ ) _m R ^a , cycloalkyl and heterocyclyl; wherein the alkyl, cycloalkyl and heterocyclyl are each independently selected from halogen, alkyl, alkane One or more substituents in oxy, haloalkyl, haloalkoxy, cyano, amine, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl replace;

R^a為環烷基或雜環基，其中該環烷基或雜環基各自獨立地視需要被選自鹵素、烷基、烷氧基、鹵烷基、鹵烷氧基、氰基、-NR^bR^c、羥基和羥烷基中的一個或多個取代基所取代； R is cycloalkyl ^or heterocyclyl, wherein the cycloalkyl or heterocyclyl are each independently selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, - NR ^b R ^c , hydroxy and hydroxyalkyl are substituted by one or more substituents;

R^b和R^c相同或不同，且各自獨立地選自氫原子、烷基、鹵烷基、羥烷基、環烷基和雜環基； R ^b and R ^c are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group;

n為0、1、2、3、4或5；且 n is 0, 1, 2, 3, 4 or 5; and

m為1、2、3、4、5或6。 m is 1, 2, 3, 4, 5 or 6.

在本揭露一些實施方案中，該通式(I)所示的化合物或其可藥用的鹽為通式(I-1)所示的化合物，或其可藥用的鹽： In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (I-1), or a pharmaceutically acceptable salt thereof:

其中， in,

L為亞(伸)烷基或

；環B為環烷基或雜環基；p為0、1、2、3、4、5或6； L is (alkylene) alkylene or

; Ring B is cycloalkyl or heterocyclyl; p is 0, 1, 2, 3, 4, 5 or 6;

環A、G₁、G₂、G₃、R¹至R⁴和n如通式(I)中所定義。 Ring A, G ₁ , G ₂ , G ₃ , R ¹ to R ⁴ and n are as defined in the general formula (I).

在本揭露一些實施方案中，該通式(I)或通式(I-1)所示的化合物或其可藥用的鹽，其中G₁為CR^2a或N原子；G₂為CR^2b或N原子；G₃為CR^3a；R^2a、R^2b和R^3a相同或不同，且各自獨立地選自氫原子、鹵素和C_1-6烷基；較佳地，G₁為CR^2a；G₂為CR^2b或N原子；G₃為CR^3a；R^2a、R^2b和R^3a相同或不同，且各自獨立地選自氫原子、鹵素和C_1-6烷基；更佳地，G₁為CH；G₂為CH或N原子；G₃為CH；最佳地，G₁為CH；G₂為N原子；G₃為CH。 In some embodiments of the present disclosure, the compound represented by general formula (I) or general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein G ₁ is CR ^2a or N atom; G ₂ is CR ^2b or N atom; G ₃ is CR ^3a ; R ^2a , R ^2b and R ^3a are the same or different, and each independently selected from hydrogen atom, halogen and C _1-6 alkyl; preferably, G ₁ is CR ^2a ; G ₂ is CR ^2b or N atom; G ₃ is CR ^3a ; R ^2a , R ^2b and R ^3a are the same or different, and each independently selected from hydrogen atom, halogen and C _1-6 alkyl; more preferably, G ₁ is CH; G ₂ is CH or N atom; G ₃ is CH; optimally, G ₁ is CH; G ₂ is N atom; G ₃ is CH.

在本揭露一些實施方案中，該通式(I)或通式(I-1)所示的化合物或其可藥用的鹽，其中G₁為CR^2a；G₂為CR^2b；G₃為CR^3a；R^2a、R^2b和R^3a相同或不同，且各自獨立地選自氫原子、鹵素和C_1-6烷基；或者G₁為N原子；G₂為CR^2b；G₃為CR^3a；R^2b和R^3a相同或不同，且各自獨立地選自氫原子、鹵素和C_1-6烷基；或者G₁為GR^2a；G₂為N原子；G₃為CR^3a；R^2a和R^3a相同或不同，且各自獨立地選自氫原子、鹵素和C_1-6烷基。 In some embodiments of the present disclosure, the compound represented by general formula (I) or general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein G ₁ is CR ^2a ; G ₂ is CR ^2b ; G ₃ is CR ^3a ; R ^2a , R ^2b and R ^3a are the same or different, and each independently selected from hydrogen atom, halogen and C _1-6 alkyl; or G ₁ is N atom; G ₂ is CR ^2b ; G ₃ is CR ^3a ; R ^2b and R ^3a are the same or different, and each independently selected from hydrogen atom, halogen and C _1-6 alkyl; or G ₁ is GR ^2a ; G ₂ is N atom; G ₃ is CR ^3a ; R ^2a and R ^3a are the same or different, and are each independently selected from a hydrogen atom, a halogen, and a C _1-6 alkyl group.

在本揭露一些實施方案中，該通式(I)或通式(I-1)所示的化合物或其可藥用的鹽，其中G₁為CR^2a；G₂為CR^2b；G₃為CR^3a；R^2a、R^2b和R^3a相同或不同，且各自獨立地選自氫原子、鹵素和C_1-6烷基；更佳地，G₁為CH；G₂為CH；G₃為CH。 In some embodiments of the present disclosure, the compound represented by general formula (I) or general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein G ₁ is CR ^2a ; G ₂ is CR ^2b ; G ₃ is CR ^3a ; R ^2a , R ^2b and R ^3a are the same or different, and each independently selected from hydrogen atom, halogen and C _1-6 alkyl; more preferably, G ₁ is CH; G ₂ is CH; G ₃ is CH.

在本揭露一些實施方案中，該通式(I)或通式(I-1)所示的化合物或其可藥用的鹽，其中R^2a、R^2b和R^3a相同或不同，且各自獨立地選自氫原子、鹵素和C_1-6烷基；較佳地，R^2a、R^2b和R^3a均為氫原子。 In some embodiments of the present disclosure, the compound represented by general formula (I) or general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein R ^2a , R ^2b and R ^3a are the same or different, and each independently is selected from hydrogen atom, halogen and C _1-6 alkyl; preferably, R ^2a , R ^2b and R ^3a are all hydrogen atoms.

在本揭露一些實施方案中，該通式(I)所示的化合物或其可藥用的鹽為通式(II)所示的化合物，或其可藥用的鹽： In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II), or a pharmaceutically acceptable salt thereof:

其中， in,

環A、R¹至R⁵和n如通式(I)中所定義。 Ring A, R ¹ to R ⁵ and n are as defined in general formula (I).

在本揭露一些實施方案中，該通式(I)、通式(I-1)或通式(II)所示的化合物或其可藥用的鹽為通式(II-1)所示的化合物，或其可藥用的鹽： In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (I-1) or general formula (II) or a pharmaceutically acceptable salt thereof is represented by general formula (II-1) The compound, or a pharmaceutically acceptable salt thereof:

其中， in,

L為亞(伸)烷基或

; Ring B is cycloalkyl or heterocyclyl; p is 0, 1, 2, 3, 4, 5 or 6;

環A、R¹至R⁴和n如通式(I)中所定義。 Ring A, R ¹ to R ⁴ and n are as defined in general formula (I).

在本揭露一些實施方案中，該通式(I)或通式(I-1)所示的化合物或其可藥用的鹽為通式(III)所示的化合物，或其可藥用的鹽： In some embodiments of the present disclosure, the compound represented by general formula (I) or general formula (I-1) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (III), or a pharmaceutically acceptable salt thereof Salt:

其中， in,

在本揭露一些實施方案中，該通式(I)、通式(I-1)或通式(III)所示的化合物或其可藥用的鹽為通式(III-1)所示的化合物，或其可藥用的鹽： In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (I-1) or general formula (III) or a pharmaceutically acceptable salt thereof is represented by general formula (III-1) The compound, or a pharmaceutically acceptable salt thereof:

其中， in,

L為亞(伸)烷基或

; Ring B is cycloalkyl or heterocyclyl; p is 0, 1, 2, 3, 4, 5 or 6;

在本揭露一些實施方案中，該通式(I)、通式(II)、通式(III)、通式(I-1)、通式(II-1)和通式(III-1)所示的化合物或其可藥用的鹽，其中環A為苯基或5至6員雜芳基；較佳地，環A為苯基。 In some embodiments of the present disclosure, the general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1) and general formula (III-1) The indicated compound or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl or 5-6 membered heteroaryl; preferably, ring A is phenyl.

在本揭露一些實施方案中，該通式(I)、通式(II)、通式(III)、通式(I-1)、通式(II-1)和通式(III-1)所示的化合物或其可藥用的鹽，其中環A選自6至10員芳基、5至10員雜芳基和3至8員環烷基；較佳地，環A為6至10員芳基或3至8員環烷基；更佳地，環A為苯基或環己基。 In some embodiments of the present disclosure, the general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1) and general formula (III-1) The indicated compound or its pharmaceutically acceptable salt, its Ring A is selected from 6 to 10 membered aryl, 5 to 10 membered heteroaryl and 3 to 8 membered cycloalkyl; preferably, ring A is 6 to 10 membered aryl or 3 to 8 membered cycloalkyl; more Preferably, ring A is phenyl or cyclohexyl.

在本揭露一些實施方案中，該通式(I)、通式(II)、通式(III)、通式(I-1)、通式(II-1)和通式(III-1)所示的化合物或其可藥用的鹽，其中R⁴為C_1-6烷基；較佳地，R⁴為甲基。 In some embodiments of the present disclosure, the general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1) and general formula (III-1) The indicated compound or a pharmaceutically acceptable salt thereof, wherein R ⁴ is C _1-6 alkyl; preferably, R ⁴ is methyl.

在本揭露一些實施方案中，該通式(I)、通式(II)和通式(III)所示的化合物或其可藥用的鹽，其中R⁵為C_1-6烷基或-(CH₂)_mR^a；R^a為3至6員環烷基；其中該3至6員環烷基視需要被選自C_1-6烷基和-NR^bR^c中的一個或多個取代基所取代；R^b和R^c相同或不同，且各自獨立地為氫原子或C_1-6烷基；m為1、2或3；較佳地，R⁵為甲基或

。 In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (II) and general formula (III) or a pharmaceutically acceptable salt thereof, wherein R ⁵ is C _1-6 alkyl or - (CH ₂ ) _m R ^a ; R ^a is 3 to 6 membered cycloalkyl; wherein the 3 to 6 membered cycloalkyl is optionally selected from one or more of C _1-6 alkyl and -NR ^b R ^c Substituents; R ^b and R ^c are the same or different, and each independently is a hydrogen atom or C _1-6 alkyl; m is 1, 2 or 3; preferably, R ⁵ is methyl or

.

在本揭露一些實施方案中，該通式(I-1)、通式(II-1)和通式(III-1)所示的化合物或其可藥用的鹽，其中L為

，環B為3至6員環烷基，p為0、1、2或3；較佳地，L為

，環B為環丙基，p為1、2或3；更佳地，L為

，環B為

，p為1。 In some embodiments of the present disclosure, the compound represented by general formula (I-1), general formula (II-1) and general formula (III-1) or a pharmaceutically acceptable salt thereof, wherein L is

, ring B is 3 to 6-membered cycloalkyl, p is 0, 1, 2 or 3; preferably, L is

, Ring B is cyclopropyl, p is 1, 2 or 3; more preferably, L is

, Ring B is

, p is 1.

在本揭露一些實施方案中，該通式(I)、通式(II)、通式(III)、通式(I-1)、通式(II-1)和通式(III-1)所示的化合物或其可藥用的鹽，其中各個R¹相同或不同，且各自獨立地選自氫原子、鹵素、C_1-6烷基、C_1-6烷氧基、C_1-6鹵烷基、C_1-6鹵烷氧基、氰基、胺基、硝基、羥基、C_1-6羥烷基、3至6員環烷基和3至6員雜環基；較佳地，各個R¹相同或不同，且各自獨立地選自氫原子、鹵素、C_1-6烷基和C_1-6鹵烷基；更佳地，各個R¹ 相同或不同，且各自獨立地選自氫原子、鹵素和C_1-6烷基；進一步佳地，各個R¹相同或不同，且各自獨立地為氫原子或鹵素；最佳地，各個R¹相同或不同，且各自獨立地為氫原子或F。 In some embodiments of the present disclosure, the general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1) and general formula (III-1) The shown compound or a pharmaceutically acceptable salt thereof, wherein each R ¹ is the same or different, and each independently selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 Haloalkyl, C _1-6 haloalkoxy, cyano, amino, nitro, hydroxyl, C _1-6 hydroxyalkyl, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocyclyl; preferred Preferably, each R ¹ is the same or different, and each independently selected from a hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl; more preferably, each R ¹ is the same or different, and each independently selected from hydrogen atom, halogen and C _1-6 alkyl; further preferably, each R ¹ is the same or different, and each independently is a hydrogen atom or halogen; most preferably, each R ¹ is the same or different, and each independently is a hydrogen atom or F.

在本揭露一些實施方案中，該通式(I)、通式(II)、通式(III)、通式(I-1)、通式(II-1)和通式(III-1)所示的化合物或其可藥用的鹽，其中R²選自氫原子、鹵素和C_1-6烷基；較佳地，R²為氫原子。 In some embodiments of the present disclosure, the general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1) and general formula (III-1) The indicated compound or a pharmaceutically acceptable salt thereof, wherein R ² is selected from hydrogen atom, halogen and C _1-6 alkyl; preferably, R ² is a hydrogen atom.

在本揭露一些實施方案中，該通式(I)、通式(II)、通式(III)、通式(I-1)、通式(II-1)和通式(III-1)所示的化合物或其可藥用的鹽，其中R³選自氫原子、鹵素和C_1-6烷基；較佳地，R³為氫原子。 In some embodiments of the present disclosure, the general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1) and general formula (III-1) The indicated compound or a pharmaceutically acceptable salt thereof, wherein R ³ is selected from hydrogen atom, halogen and C _1-6 alkyl; preferably, R ³ is a hydrogen atom.

在本揭露一些實施方案中，該通式(I)、通式(II)、通式(III)、通式(I-1)、通式(II-1)和通式(III-1)所示的化合物或其可藥用的鹽，其中n為0、1或2；較佳地，n為0或1。 In some embodiments of the present disclosure, the general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1) and general formula (III-1) The indicated compound or a pharmaceutically acceptable salt thereof, wherein n is 0, 1 or 2; preferably, n is 0 or 1.

在本揭露一些實施方案中，該通式(I)所示的化合物或其可藥用的鹽，其中，環A為苯基；G₁為CR^2a；G₂為CR^2b；G₃為CR^3a；R^2a、R^2b和R^3a相同或不同，且各自獨立地選自氫原子、鹵素和C_1-6烷基；R⁴為甲基；R⁵為甲基或

；各個R¹相同或不同，且各自獨立地選自氫原子、鹵素、C_1-6烷基和C_1-6鹵烷基；R²選自氫原子、鹵素和C_1-6烷基；R³選自氫原子、鹵素和C_1-6烷基；且n為0或1。 In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein, Ring A is phenyl; G ₁ is CR ^2a ; G ₂ is CR ^2b ; G ₃ is CR ^3a ; R ^2a , R ^2b and R ^3a are the same or different, and each independently selected from hydrogen atom, halogen and C _1-6 alkyl; R ⁴ is methyl; R ⁵ is methyl or

; Each R ¹ is the same or different, and is independently selected from hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl; R ² is selected from hydrogen atom, halogen and C _1-6 alkyl; R ³ is selected from hydrogen atom, halogen and C _1-6 alkyl; and n is 0 or 1.

在本揭露一些實施方案中，該通式(I)所示的化合物或其可藥用的鹽，其中，環A為苯基或環己基；G₁為CR^2a；G₂為CR^2b或N原子；G₃為CR^3a；R^2a、R^2b和R^3a相同或不同，且各自獨立地選自氫原子、鹵素和C_1-6烷基；R⁴為甲基；R⁵為甲基或

；各個R¹相同或不同，且各自獨立地選自氫原子、鹵素、C_1-6烷基和C_1-6鹵烷基；R²選自氫原子、鹵素和C_1-6烷基；R³選自氫原子、鹵素和C_1-6烷基；且n為0或1。 In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein, ring A is phenyl or cyclohexyl; G ₁ is CR ^2a ; G ₂ is CR ^2b or N atom; G ₃ is CR ^3a ; R ^2a , R ^2b and R ^3a are the same or different, and each independently selected from hydrogen atom, halogen and C _1-6 alkyl; R ⁴ is methyl; R ⁵ is methyl or

在本揭露一些實施方案中，該通式(I)所示的化合物或其可藥用的鹽，其中，環A為苯基或環己基；G₁為CH；G₂為CH或N原子；G₃為CH；R⁴為甲基；R⁵為甲基或

；各個R¹相同或不同，且各自獨立地為氫原子或鹵素；R²選自氫原子、鹵素和C_1-6烷基；R³選自氫原子、鹵素和C_1-6烷基；且n為0或1。 In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein, ring A is phenyl or cyclohexyl; G ₁ is CH; G ₂ is CH or N atom; G ₃ is CH; R ⁴ is methyl; R ⁵ is methyl or

; Each R ¹ is the same or different, and each independently is a hydrogen atom or a halogen; R ² is selected from a hydrogen atom, a halogen and a C _1-6 alkyl group; R ³ is selected from a hydrogen atom, a halogen and a C _1-6 alkyl group; And n is 0 or 1.

；各個R¹相同或不同，且各自獨立地為氫原子或鹵素；R²為氫原子；R³為氫原子；且n為0或1。 In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein, ring A is phenyl or cyclohexyl; G ₁ is CH; G ₂ is CH or N atom; G ₃ is CH; R ⁴ is methyl; R ⁵ is methyl or

each R ¹ is the same or different, and each independently is a hydrogen atom or a halogen; R ² is a hydrogen atom; R ³ is a hydrogen atom; and n is 0 or 1.

在本揭露一些實施方案中，該通式(II)所示的化合物或其可藥用的鹽，其中，環A為苯基；R⁴為甲基；R⁵為甲基或

；各個R¹相同或不同，且各自獨立地選自氫原子、鹵素、C_1-6烷基和C_1-6鹵烷基；R²選自氫原子、鹵素和C_1-6烷基；R³選自氫原子、鹵素和C_1-6烷基；且n為0或1。 In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein, ring A is phenyl; R ⁴ is methyl; R ⁵ is methyl or

在本揭露一些實施方案中，該通式(II)所示的化合物或其可藥用的鹽，其中，環A為苯基或環己基；R⁴為甲基；R⁵為甲基或

；各個R¹相同或不同，且各自獨立地選自氫原子、鹵素、C_1-6烷基和C_1-6鹵烷基；R²選自氫原子、鹵素和C_1-6烷基；R³選自氫原子、鹵素和C_1-6烷基；且n為0或1。 In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein, ring A is phenyl or cyclohexyl; R ⁴ is methyl; R ⁵ is methyl or

；各個R¹相同或不同，且各自獨立地為氫原子或鹵素；R²為氫原子；R³為氫原子；且n為0或1。 In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein, ring A is phenyl or cyclohexyl; R ⁴ is methyl; R ⁵ is methyl or

在本揭露一些實施方案中，該通式(III)所示的化合物或其可藥用的鹽，其中，環A為苯基；R⁴為甲基；R⁵為甲基；各個R¹相同或不同，且各自獨立地選自氫原子、鹵素、C_1-6烷基和C_1-6鹵烷基；R²選自氫原子、鹵素和C_1-6烷基；R³選自氫原子、鹵素和C_1-6烷基；且n為0或1。 In some embodiments of the present disclosure, the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof, wherein, ring A is phenyl; R ⁴ is methyl; R ⁵ is methyl; each R ¹ is the same or different, and each independently selected from hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl; R ² selected from hydrogen atom, halogen and C _1-6 alkyl; R ³ selected from hydrogen atom, halogen and C _1-6 alkyl; and n is 0 or 1.

在本揭露一些實施方案中，該通式(III)所示的化合物或其可藥用的鹽，其中，環A為苯基或環己基；R⁴為甲基；R⁵為甲基；各個R¹相同或不同，且各自獨立地選自氫原子、鹵素、C_1-6烷基和C_1-6鹵烷基；R²選自氫原子、鹵素和C_1-6烷基；R³選自氫原子、鹵素和C_1-6烷基；且n為0或1。 In some embodiments of the present disclosure, the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof, wherein, ring A is phenyl or cyclohexyl; R ⁴ is methyl; R ⁵ is methyl; each R ¹ is the same or different, and each independently selected from hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl; R ² is selected from hydrogen atom, halogen and C _1-6 alkyl; R ³ selected from hydrogen atom, halogen and C _1-6 alkyl; and n is 0 or 1.

在本揭露一些實施方案中，該通式(III)所示的化合物或其可藥用的鹽，其中，環A為苯基或環己基；R⁴為甲基；R⁵為甲基；各個R¹相同或不同，且各自獨立地為氫原子或鹵素；R²為氫原子；R³為氫原子；且n為0或1。 In some embodiments of the present disclosure, the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof, wherein, ring A is phenyl or cyclohexyl; R ⁴ is methyl; R ⁵ is methyl; each R ¹ is the same or different, and each independently is a hydrogen atom or a halogen; R ² is a hydrogen atom; R ³ is a hydrogen atom; and n is 0 or 1.

表A 本揭露的典型化合物包括但不限於：

Table A Typical compounds of the present disclosure include, but are not limited to:

本揭露的另一方面關於通式(IA)所示的化合物或其鹽： Another aspect of the present disclosure relates to a compound represented by general formula (IA) or a salt thereof:

其中， in,

G₁、G₂、G₃和R²至R⁵如通式(I)中所定義。其為製備通式(I)所示化合物的中間體。 G ₁ , G ₂ , G ₃ and R ² to R ⁵ are as defined in the general formula (I). It is an intermediate for preparing the compound represented by general formula (I).

本揭露的另一方面關於通式(I-1A)所示的化合物或其鹽： Another aspect of the present disclosure relates to the compound or salt thereof represented by the general formula (I-1A):

其中， in,

R^w為胺基保護基，較佳為Boc； R ^w is an amino protecting group, preferably Boc;

L為亞(伸)烷基或

; Ring B is cycloalkyl or heterocyclyl; p is 0, 1, 2, 3, 4, 5 or 6;

G₁、G₂、G₃和R²至R⁴如通式(I-1)中所定義。其為製備通式(I-1)所示化合物的中間體。 G ₁ , G ₂ , G ₃ and R ² to R ⁴ are as defined in the general formula (I-1). It is an intermediate for preparing the compound represented by the general formula (I-1).

本揭露的另一方面關於通式(IIA)所示的化合物或其鹽： Another aspect of the present disclosure relates to compounds represented by general formula (IIA) or salts thereof:

其中， in,

R²至R⁵如通式(II)中所定義。其為製備通式(II)所示化合物的中間體。 R ² to R ⁵ are as defined in the general formula (II). It is an intermediate for preparing the compound represented by general formula (II).

本揭露的另一方面關於通式(II-1A)所示的化合物或其鹽： Another aspect of the present disclosure relates to the compound represented by the general formula (II-1A) or a salt thereof:

其中， in,

L為亞(伸)烷基或

; Ring B is cycloalkyl or heterocyclyl; p is 0, 1, 2, 3, 4, 5 or 6;

R²至R⁴如通式(II-1)中所定義。其為製備通式(II-1)所示化合物的中間體。 R ² to R ⁴ are as defined in the general formula (II-1). It is an intermediate for preparing the compound represented by the general formula (II-1).

本揭露的另一方面關於通式(IIIA)所示的化合物或其鹽： Another aspect of the present disclosure relates to the compound represented by general formula (IIIA) or a salt thereof:

其中， in,

R²至R⁵如通式(III)中所定義。其為製備通式(III)所示化合物的中間體。 R ² to R ⁵ are as defined in the general formula (III). It is an intermediate for preparing the compound represented by general formula (III).

本揭露的另一方面關於通式(III-1A)所示的化合物或其鹽： Another aspect of the present disclosure relates to the compound represented by the general formula (III-1A) or a salt thereof:

其中， in,

L為亞(伸)烷基或

; Ring B is cycloalkyl or heterocyclyl; p is 0, 1, 2, 3, 4, 5 or 6;

R²至R⁴如通式(III-1)中所定義。其為製備通式(III-1)所示化合物的中間體。 R ² to R ⁴ are as defined in the general formula (III-1). It is an intermediate for preparing the compound represented by general formula (III-1).

本揭露的另一方面關於通式(IC)所示的化合物或其鹽： Another aspect of the present disclosure relates to compounds represented by general formula (IC) or salts thereof:

其中， in,

Y為鹵素；較佳為溴原子； Y is a halogen; preferably a bromine atom;

本揭露的另一方面關於通式(IIC)所示的化合物或其鹽： Another aspect of the present disclosure relates to compounds represented by general formula (IIC) or salts thereof:

其中， in,

本揭露的另一方面關於通式(IIIC)所示的化合物或其鹽： Another aspect of the present disclosure is about the compound represented by the general formula (IIIC) or a salt thereof:

其中， in,

本揭露的另一方面關於通式(IAa)所示的化合物或其鹽： Another aspect of the present disclosure relates to a compound represented by general formula (IAa) or a salt thereof:

其中， in,

本揭露的另一方面關於通式(IIAa)所示的化合物或其鹽： Another aspect of the present disclosure relates to compounds represented by general formula (IIAa) or salts thereof:

其中， in,

本揭露的另一方面關於通式(IIIAa)所示的化合物或其鹽： Another aspect of the present disclosure relates to the compound or salt thereof represented by the general formula (IIIAa):

其中， in,

表B 本揭露的典型中間體化合物包括但不限於：

Table B Typical intermediate compounds of the present disclosure include, but are not limited to:

本揭露的另一方面關於一種製備通式(I)所示的化合物或其可藥用的鹽的方法，該方法包括： Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

通式(IA)的化合物或其鹽與通式(IB)的化合物或其鹽發生醯化反應，得到通式(I)的化合物或其可藥用的鹽， Acylation reaction of the compound of general formula (IA) or its salt with the compound of general formula (IB) or its salt to obtain the compound of general formula (I) or its pharmaceutically acceptable salt,

其中， in,

X為鹵素；較佳為氯原子； X is a halogen; preferably a chlorine atom;

環A、G₁、G₂、G₃、R¹至R⁵和n如通式(I)中所定義。 Ring A, G ₁ , G ₂ , G ₃ , R ¹ to R ⁵ and n are as defined in the general formula (I).

本揭露的另一方面關於一種製備通式(II)所示的化合物或其可藥用的鹽的方法，該方法包括： Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

通式(IIA)的化合物或其鹽與通式(IB)的化合物或其鹽發生醯化反應，得到通式(II)的化合物或其可藥用的鹽， Acylation reaction of the compound of general formula (IIA) or its salt with the compound of general formula (IB) or its salt to obtain the compound of general formula (II) or its pharmaceutically acceptable salt,

其中， in,

X為鹵素；較佳為氯原子； X is a halogen; preferably a chlorine atom;

環A、R¹至R⁵和n如通式(II)中所定義。 Ring A, R ¹ to R ⁵ and n are as defined in general formula (II).

本揭露的另一方面關於一種製備通式(III)所示的化合物或其可藥用的鹽的方法，該方法包括： Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

通式(IIIA)的化合物或其鹽與通式(IB)的化合物或其鹽發生醯化反應，得到通式(III)的化合物或其可藥用的鹽， The compound of general formula (IIIA) or its salt is reacted with the compound of general formula (IB) or its salt to produce the compound of general formula (III) or its pharmaceutically acceptable salt,

其中， in,

X為鹵素；較佳為氯原子； X is a halogen; preferably a chlorine atom;

環A、R¹至R⁵和n如通式(III)中所定義。 Ring A, R ¹ to R ⁵ and n are as defined in general formula (III).

本揭露的另一方面關於一種製備通式(I-1)所示的化合物，或其可藥用的鹽的製備方法，該方法包括： Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I-1), or a pharmaceutically acceptable salt thereof, the method comprising:

(a)通式(I-1A)的化合物或其鹽與通式(IB)的化合物或其鹽發生醯化反應，得到通式(I-1Aa)的化合物或其可藥用的鹽； (a) acylation reaction of a compound of general formula (I-1A) or a salt thereof with a compound of general formula (IB) or a salt thereof to obtain a compound of general formula (I-1Aa) or a pharmaceutically acceptable salt thereof;

(b)通式(I-1Aa)的化合物或其可藥用的鹽發生脫保護反應得到通式(I-1)的化合物或其可藥用的鹽； (b) deprotecting the compound of general formula (I-1Aa) or its pharmaceutically acceptable salt to obtain the compound of general formula (I-1) or its pharmaceutically acceptable salt;

其中， in,

X為鹵素；較佳為氯原子； X is a halogen; preferably a chlorine atom;

L為亞(伸)烷基或

; Ring B is cycloalkyl or heterocyclyl; p is 0, 1, 2, 3, 4, 5 or 6;

環A、G₁、G₂、G₃、R¹至R⁴和n如通式(I-1)中所定義。 Ring A, G ₁ , G ₂ , G ₃ , R ¹ to R ⁴ and n are as defined in the general formula (I-1).

本揭露的另一方面關於一種製備通式(II-1)所示的化合物，或其可藥用的鹽的方法，該方法包括： Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II-1), or a pharmaceutically acceptable salt thereof, the method comprising:

(a)通式(II-1A)的化合物或其鹽與通式(IB)的化合物或其鹽發生醯化反應，得到通式(II-1Aa)的化合物或其可藥用的鹽； (a) acylation reaction of a compound of general formula (II-1A) or a salt thereof with a compound of general formula (IB) or a salt thereof to obtain a compound of general formula (II-1Aa) or a pharmaceutically acceptable salt thereof;

(b)通式(II-1Aa)的化合物或其可藥用的鹽發生脫保護反應得到通式(II-1)的化合物或其可藥用的鹽； (b) deprotecting the compound of general formula (II-1Aa) or its pharmaceutically acceptable salt to obtain the compound of general formula (II-1) or its pharmaceutically acceptable salt;

其中， in,

X為鹵素；較佳為氯原子； X is a halogen; preferably a chlorine atom;

L為亞(伸)烷基或

; Ring B is cycloalkyl or heterocyclyl; p is 0, 1, 2, 3, 4, 5 or 6;

環A、R¹至R⁴和n如通式(II-1)中所定義。 Ring A, R ¹ to R ⁴ and n are as defined in the general formula (II-1).

本揭露的另一方面關於一種製備通式(III-1)所示的化合物，或其可藥用的鹽的方法，該方法包括： Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III-1), or a pharmaceutically acceptable salt thereof, the method comprising:

(a)通式(III-1A)的化合物或其鹽與通式(IB)的化合物或其鹽發生醯化反應，得到通式(III-1Aa)的化合物或其可藥用的鹽； (a) acylation reaction of a compound of general formula (III-1A) or a salt thereof with a compound of general formula (IB) or a salt thereof to obtain a compound of general formula (III-1Aa) or a pharmaceutically acceptable salt thereof;

(b)通式(III-1Aa)的化合物或其可藥用的鹽發生脫保護反應得到通式(III-1)的化合物或其可藥用的鹽； (b) deprotection reaction of the compound of general formula (III-1Aa) or its pharmaceutically acceptable salt to obtain the compound of general formula (III-1) or its pharmaceutically acceptable salt;

其中， in,

X為鹵素；較佳為氯原子； X is a halogen; preferably a chlorine atom;

L為亞(伸)烷基或

; Ring B is cycloalkyl or heterocyclyl; p is 0, 1, 2, 3, 4, 5 or 6;

環A、R¹至R⁴和n如通式(III-1)中所定義。 Ring A, R ¹ to R ⁴ and n are as defined in the general formula (III-1).

通式(IC)的化合物或其鹽與通式(ID)的化合物或其鹽發生偶聯反應，得到通式(I)的化合物或其可藥用的鹽， A compound of general formula (IC) or a salt thereof is coupled with a compound of general formula (ID) or a salt thereof to obtain a compound of general formula (I) or a pharmaceutically acceptable salt thereof,

其中， in,

Y為鹵素；較佳為溴原子； Y is a halogen; preferably a bromine atom;

通式(IIC)的化合物或其鹽與通式(ID)的化合物或其鹽發生偶聯反應，得到通式(II)的化合物或其可藥用的鹽， A compound of general formula (IIC) or a salt thereof is coupled with a compound of general formula (ID) or a salt thereof to obtain a compound of general formula (II) or a pharmaceutically acceptable salt thereof,

其中， in,

Y為鹵素；較佳為溴原子； Y is a halogen; preferably a bromine atom;

通式(IIIC)的化合物或其鹽與通式(ID)的化合物或其鹽發生偶聯反應，得到通式(III)的化合物或其可藥用的鹽， A compound of general formula (IIIC) or a salt thereof is coupled with a compound of general formula (ID) or a salt thereof to obtain a compound of general formula (III) or a pharmaceutically acceptable salt thereof,

其中， in,

Y為鹵素；較佳為溴原子； Y is a halogen; preferably a bromine atom;

通式(IAa)的化合物或其鹽與通式(IBb)的化合物或其鹽發生醯胺化反應，得到通式(I)的化合物或其可藥用的鹽， A compound of general formula (IAa) or a salt thereof and a compound of general formula (IBb) or a salt thereof undergo an amidation reaction to obtain a compound of general formula (I) or a pharmaceutically acceptable salt thereof,

其中， in,

通式(IIAa)的化合物或其鹽與通式(IBb)的化合物或其鹽發生醯胺化反應，得到通式(II)的化合物或其可藥用的鹽， A compound of general formula (IIAa) or a salt thereof and a compound of general formula (IBb) or a salt thereof undergo an amidation reaction to obtain a compound of general formula (II) or a pharmaceutically acceptable salt thereof,

其中， in,

通式(IIIAa)的化合物或其鹽與通式(IBb)的化合物或其鹽發生醯胺化反應，得到通式(III)的化合物或其可藥用的鹽， A compound of general formula (IIIAa) or a salt thereof and a compound of general formula (IBb) or a salt thereof undergo an amidation reaction to obtain a compound of general formula (III) or a pharmaceutically acceptable salt thereof,

其中， in,

本揭露的另一方面關於一種醫藥組成物，該醫藥組成物含有本揭露通式(I)、通式(II)、通式(III)、通式(I-1)、通式(II-1)、通式(III-1)和表A中所示的化合物或其可藥用的鹽，以及一種或多種藥學上可接受的載體、稀釋劑或賦形劑。 Another aspect of the present disclosure relates to a pharmaceutical composition, which contains the general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II- 1), the compound shown in general formula (III-1) and Table A or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

本揭露進一步關於通式(I)、通式(II)、通式(III)、通式(I-1)、通式(II-1)、通式(III-1)和表A中所示的化合物或其可藥用的鹽、或包括其的醫藥組成物在製備用於抑制蛋白激酶的藥物中的用途。 The present disclosure further relates to general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1), general formula (III-1) and table A Use of the indicated compound or its pharmaceutically acceptable salt, or a pharmaceutical composition comprising it in the preparation of a medicament for inhibiting protein kinase.

本揭露進一步關於通式(I)、通式(II)、通式(III)、通式(I-1)、通式(II-1)、通式(III-1)和表A中所示的化合物或其可藥用的鹽、或包括其的醫藥組成物在製備用於治療和/或預防疾病、病症和綜合症的藥物中的用途；具體為在製備用於藉由抑制蛋白激酶來治療和/或預防的疾病、病症和綜合症的藥物中的用途。其中該疾病、病症和綜合症較佳選自肉瘤、多發性骨髓瘤、白血病、黏液瘤、橫紋肌瘤、平滑肌瘤、纖維瘤、脂肪瘤、畸胎瘤、咽喉癌、口腔癌、肺癌、肺泡癌、淋巴瘤、間皮瘤、結直腸癌、小腸癌、胃癌、食道癌、胰腺癌、乳腺癌、子宮內膜癌、卵巢癌、輸卵管癌、宮頸癌、腎癌、膀胱癌、***癌、睾丸癌、肝癌、膽管癌、神經膠質瘤、神經母細胞瘤、黑色素瘤、皮膚癌、基底細胞癌、鱗狀細胞癌、甲狀腺癌、頭頸癌、唾液腺癌、銀屑病、胃腸道間質瘤(GIST)、動脈粥樣硬化和肺纖維化；其中該咽喉癌較佳為鼻咽癌；該肉瘤較佳為骨肉瘤或軟骨肉瘤；該結直腸癌較佳為結腸癌或直腸癌；該纖維瘤較佳為神經纖維瘤。 The present disclosure further relates to general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1), general formula (III-1) and table A The compounds shown or their pharmaceutically acceptable salts, or pharmaceutical compositions comprising them are used in the preparation of medicaments for the treatment and/or prevention of diseases, disorders and syndromes In particular, the use in the preparation of medicaments for treating and/or preventing diseases, disorders and syndromes by inhibiting protein kinases. Wherein the diseases, disorders and syndromes are preferably selected from the group consisting of sarcoma, multiple myeloma, leukemia, myxoma, rhabdomyoma, leiomyoma, fibroma, lipoma, teratoma, throat cancer, oral cavity cancer, lung cancer, alveolar Cancer, lymphoma, mesothelioma, colorectal cancer, small intestine cancer, stomach cancer, esophagus cancer, pancreatic cancer, breast cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, cervical cancer, kidney cancer, bladder cancer, prostate cancer, Testicular cancer, liver cancer, cholangiocarcinoma, glioma, neuroblastoma, melanoma, skin cancer, basal cell carcinoma, squamous cell carcinoma, thyroid cancer, head and neck cancer, salivary gland cancer, psoriasis, gastrointestinal stromal tumor (GIST), atherosclerosis and pulmonary fibrosis; wherein the throat cancer is preferably nasopharyngeal carcinoma; the sarcoma is preferably osteosarcoma or chondrosarcoma; the colorectal cancer is preferably colon cancer or rectal cancer; The tumor is preferably a neurofibroma.

本揭露進一步關於通式(I)、通式(II)、通式(III)、通式(I-1)、通式(II-1)、通式(III-1)和表A中所示的化合物或其可藥用的鹽、或包括其的醫藥組成物在製備用於治療和/或預防腫瘤的藥物中的用途，其中該腫瘤較佳為癌症，更佳選自肉瘤、多發性骨髓瘤、白血病、黏液瘤、橫紋肌瘤、平滑肌瘤、纖維瘤、脂肪瘤、畸胎瘤、咽喉癌、口腔癌、肺癌、肺泡癌、淋巴瘤、間皮瘤、結直腸癌、小腸癌、胃癌、食道癌、胰腺癌、乳腺癌、子宮內膜癌、卵巢癌、輸卵管癌、宮頸癌、腎癌、膀胱癌、***癌、睾丸癌、肝癌、膽管癌、神經膠質瘤、神經母細胞瘤、黑色素瘤、皮膚癌、基底細胞癌、鱗狀細胞癌、甲狀腺癌、頭頸癌、唾液腺癌和胃腸道間質瘤(GIST)；其中該咽喉癌較佳為鼻咽癌；該肉瘤較佳為骨肉瘤或軟骨肉瘤；該結直腸癌較佳為結腸癌或直腸癌；該纖維瘤較佳為神經纖維瘤。 The present disclosure further relates to general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1), general formula (III-1) and table A Use of the compound or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it, in the preparation of medicines for treating and/or preventing tumors, wherein the tumor is preferably cancer, more preferably selected from sarcoma, multiple Myeloma, leukemia, myxoma, rhabdomyoma, leiomyoma, fibroma, lipoma, teratoma, throat cancer, oral cancer, lung cancer, alveolar cancer, lymphoma, mesothelioma, colorectal cancer, small bowel cancer, Gastric cancer, esophageal cancer, pancreatic cancer, breast cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, cervical cancer, kidney cancer, bladder cancer, prostate cancer, testicular cancer, liver cancer, bile duct cancer, glioma, neuroblastoma , melanoma, skin cancer, basal cell carcinoma, squamous cell carcinoma, thyroid cancer, head and neck cancer, salivary gland cancer and gastrointestinal stromal tumor (GIST); wherein the throat cancer is preferably nasopharyngeal carcinoma; the sarcoma is preferably Osteosarcoma or chondrosarcoma; the colorectal cancer is preferably colon cancer or rectal cancer; the fibroma is preferably neurofibroma.

本揭露進一步關於一種抑制蛋白激酶的方法，其包括給予所需患者治療有效量的通式(I)、通式(II)、通式(III)、通式(I-1)、通式 (II-1)、通式(III-1)和表A所示的化合物或其可藥用的鹽、或包括其的醫藥組成物。 The disclosure further relates to a method of inhibiting protein kinase, which comprises administering a therapeutically effective amount of the general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1), the compound represented by the general formula (III-1) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition including the same.

本揭露進一步關於一種治療和/或預防疾病、病症和綜合症的方法，具體為一種治療和/或預防藉由抑制蛋白激酶來治療和/或預防的疾病、病症和綜合症的方法，其包括給予所需患者治療有效量的通式(I)、通式(II)、通式(III)、通式(I-1)、通式(II-1)、通式(III-1)和表A所示的化合物或其可藥用的鹽、或包括其的醫藥組成物。其中該疾病、病症和綜合症較佳選自肉瘤、多發性骨髓瘤、白血病、黏液瘤、橫紋肌瘤、平滑肌瘤、纖維瘤、脂肪瘤、畸胎瘤、咽喉癌、口腔癌、肺癌、肺泡癌、淋巴瘤、間皮瘤、結直腸癌、小腸癌、胃癌、食道癌、胰腺癌、乳腺癌、子宮內膜癌、卵巢癌、輸卵管癌、宮頸癌、腎癌、膀胱癌、***癌、睾丸癌、肝癌、膽管癌、神經膠質瘤、神經母細胞瘤、黑色素瘤、皮膚癌、基底細胞癌、鱗狀細胞癌、甲狀腺癌、頭頸癌、唾液腺癌、銀屑病、胃腸道間質瘤(GIST)、動脈粥樣硬化和肺纖維化；其中該咽喉癌較佳為鼻咽癌；該肉瘤較佳為骨肉瘤或軟骨肉瘤；該結直腸癌較佳為結腸癌或直腸癌；該纖維瘤較佳為神經纖維瘤。 The present disclosure further relates to a method of treating and/or preventing diseases, disorders and syndromes, in particular a method of treating and/or preventing diseases, disorders and syndromes treated and/or prevented by inhibiting protein kinases, comprising General formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1), general formula (III-1) and A compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. Wherein the diseases, disorders and syndromes are preferably selected from the group consisting of sarcoma, multiple myeloma, leukemia, myxoma, rhabdomyoma, leiomyoma, fibroma, lipoma, teratoma, throat cancer, oral cavity cancer, lung cancer, alveolar Cancer, lymphoma, mesothelioma, colorectal cancer, small intestine cancer, stomach cancer, esophagus cancer, pancreatic cancer, breast cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, cervical cancer, kidney cancer, bladder cancer, prostate cancer, Testicular cancer, liver cancer, cholangiocarcinoma, glioma, neuroblastoma, melanoma, skin cancer, basal cell carcinoma, squamous cell carcinoma, thyroid cancer, head and neck cancer, salivary gland cancer, psoriasis, gastrointestinal stromal tumor (GIST), atherosclerosis and pulmonary fibrosis; wherein the throat cancer is preferably nasopharyngeal carcinoma; the sarcoma is preferably osteosarcoma or chondrosarcoma; the colorectal cancer is preferably colon cancer or rectal cancer; The tumor is preferably a neurofibroma.

本揭露進一步關於一種治療和/或預防腫瘤的方法，其包括給予所需患者治療有效量的通式(I)、通式(II)、通式(III)、通式(I-1)、通式(II-1)、通式(III-1)和表A所示的化合物或其可藥用的鹽、或包括其的醫藥組成物。其中該腫瘤較佳為癌症，更佳選自肉瘤、多發性骨髓瘤、白血病、黏液瘤、橫紋肌瘤、平滑肌瘤、纖維瘤、脂肪瘤、畸胎瘤、咽喉癌、口腔癌、肺癌、淋巴瘤、間皮瘤、結直腸癌、小腸癌、胃癌、食道癌、胰腺癌、乳腺癌、子宮內膜癌、卵巢癌、輸卵管癌、宮頸癌、腎癌、膀胱癌、***癌、睾丸癌、肝癌、膽管癌、神經膠質瘤、神經母細胞瘤、黑色素瘤、皮膚癌、基底細胞癌、鱗狀細胞癌、甲狀腺癌、頭頸癌、唾液腺癌和胃腸道間質瘤(GIST)；其中該咽喉癌較佳為鼻咽癌；該肉瘤較佳為骨肉瘤或軟骨肉瘤；該結直腸癌較佳為結腸癌或直腸癌；該纖維瘤較佳為神經纖維瘤。 The disclosure further relates to a method for treating and/or preventing tumors, which includes administering a therapeutically effective amount of general formula (I), general formula (II), general formula (III), general formula (I-1), A compound represented by general formula (II-1), general formula (III-1) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. Wherein the tumor is preferably cancer, more preferably selected from the group consisting of sarcoma, multiple myeloma, leukemia, myxoma, rhabdomyoma, leiomyoma, fibroma, lipoma, teratoma, throat cancer, oral cavity cancer, lung cancer, lymphoma tumor, mesothelioma, colorectal cancer, small intestine cancer, stomach cancer, esophageal cancer, pancreatic cancer, breast cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, cervical cancer, kidney cancer, bladder cancer, prostate cancer, testicular cancer, Liver cancer, cholangiocarcinoma, glioma, neuroblastoma, black melanoma, skin cancer, basal cell carcinoma, squamous cell carcinoma, thyroid cancer, head and neck cancer, salivary gland cancer and gastrointestinal stromal tumor (GIST); wherein the throat cancer is preferably nasopharyngeal carcinoma; the sarcoma is preferably bone tumor or chondrosarcoma; the colorectal cancer is preferably colon cancer or rectal cancer; the fibroma is preferably neurofibroma.

本揭露進一步關於一種通式(I)、通式(II)、通式(III)、通式(I-1)、通式(II-1)、通式(III-1)和表A所示的化合物或其可藥用的鹽、或包括其的醫藥組成物，其用作藥物。 The disclosure is further related to a general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1), general formula (III-1) and table A The indicated compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, is used as a medicament.

本揭露進一步關於一種通式(I)、通式(II)、通式(III)、通式(I-1)、通式(II-1)、通式(III-1)和表A所示的化合物或其可藥用的鹽、或包括其的醫藥組成物，其用作抑制蛋白激酶的藥物。 The disclosure is further related to a general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1), general formula (III-1) and table A The compound or its pharmaceutically acceptable salt, or a pharmaceutical composition comprising it, is used as a drug for inhibiting protein kinase.

本揭露進一步關於一種通式(I)、通式(II)、通式(III)、通式(I-1)、通式(II-1)、通式(III-1)和表A所示的化合物或其可藥用的鹽、或包括其的醫藥組成物，其用作治療和/或預防疾病、病症和綜合症的藥物，具體為用作治療和/或預防藉由抑制蛋白激酶來治療和/或預防的疾病、病症和綜合症的藥物。其中該疾病、病症和綜合症較佳選自肉瘤、多發性骨髓瘤、白血病、黏液瘤、橫紋肌瘤、平滑肌瘤、纖維瘤、脂肪瘤、畸胎瘤、咽喉癌、口腔癌、肺癌、肺泡癌、淋巴瘤、間皮瘤、結直腸癌、小腸癌、胃癌、食道癌、胰腺癌、乳腺癌、子宮內膜癌、卵巢癌、輸卵管癌、宮頸癌、腎癌、膀胱癌、***癌、睾丸癌、肝癌、膽管癌、神經膠質瘤、神經母細胞瘤、黑色素瘤、皮膚癌、基底細胞癌、鱗狀細胞癌、甲狀腺癌、頭頸癌、唾液腺癌、銀屑病、胃腸道間質瘤(GIST)、動脈粥樣硬化和肺纖維化；其中該咽喉癌較佳為鼻咽癌；該肉瘤較佳為骨肉瘤或軟骨肉瘤；該結直腸癌較佳為結腸癌或直腸癌；該纖維瘤較佳為神經纖維瘤。 The disclosure is further related to a general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1), general formula (III-1) and table A Compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, for use as a medicament for the treatment and/or prevention of diseases, disorders and syndromes, in particular for use in the treatment and/or prevention of protein kinases by inhibiting Drugs to treat and/or prevent diseases, conditions and syndromes. Wherein the diseases, disorders and syndromes are preferably selected from the group consisting of sarcoma, multiple myeloma, leukemia, myxoma, rhabdomyoma, leiomyoma, fibroma, lipoma, teratoma, throat cancer, oral cavity cancer, lung cancer, alveolar Cancer, lymphoma, mesothelioma, colorectal cancer, small intestine cancer, stomach cancer, esophagus cancer, pancreatic cancer, breast cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, cervical cancer, kidney cancer, bladder cancer, prostate cancer, Testicular cancer, liver cancer, cholangiocarcinoma, glioma, neuroblastoma, melanoma, skin cancer, basal cell carcinoma, squamous cell carcinoma, thyroid cancer, head and neck cancer, salivary gland cancer, psoriasis, gastrointestinal stromal tumor (GIST), atherosclerosis and pulmonary fibrosis; wherein the throat cancer is preferably nasopharyngeal carcinoma; the sarcoma is preferably osteosarcoma or chondrosarcoma; the colorectal cancer is preferably colon cancer or rectal cancer; The tumor is preferably a neurofibroma.

本揭露進一步關於一種通式(I)、通式(II)、通式(III)、通式(I-1)、通式(II-1)、通式(III-1)和表A所示的化合物或其可藥用的鹽、或包括其的醫藥組成物，其用作治療和/或預防腫瘤的藥物，其中該腫瘤較佳為癌症，更佳選自肉瘤、多發性骨髓瘤、白血病、黏液瘤、橫紋肌瘤、平滑肌瘤、纖維瘤、脂肪瘤、畸胎瘤、咽喉癌、口腔癌、肺癌、肺泡癌、淋巴瘤、間皮瘤、結直腸癌、小腸癌、胃癌、食道癌、胰腺癌、乳腺癌、子宮內膜癌、卵巢癌、輸卵管癌、宮頸癌、腎癌、膀胱癌、***癌、睾丸癌、肝癌、膽管癌、神經膠質瘤、神經母細胞瘤、黑色素瘤、皮膚癌、基底細胞癌、鱗狀細胞癌、甲狀腺癌、頭頸癌、唾液腺癌和胃腸道間質瘤(GIST)；其中該咽喉癌較佳為鼻咽癌；該肉瘤較佳為骨肉瘤或軟骨肉瘤；該結直腸癌較佳為結腸癌或直腸癌；該纖維瘤較佳為神經纖維瘤。 The disclosure is further related to a general formula (I), general formula (II), general formula (III), general formula (I-1), general formula (II-1), general formula (III-1) and table A The compound or its pharmaceutically acceptable salt, or the pharmaceutical composition comprising it, it is used as the medicine for treating and/or preventing tumor, wherein the tumor is preferably cancer, more preferably selected from sarcoma, multiple myeloma, Leukemia, myxoma, rhabdomyoma, leiomyoma, fibroma, lipoma, teratoma, throat cancer, oral cancer, lung cancer, alveolar cancer, lymphoma, mesothelioma, colorectal cancer, small intestine cancer, stomach cancer, esophagus Cancer, pancreatic cancer, breast cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, cervical cancer, kidney cancer, bladder cancer, prostate cancer, testicular cancer, liver cancer, bile duct cancer, glioma, neuroblastoma, melanoma , skin cancer, basal cell carcinoma, squamous cell carcinoma, thyroid cancer, head and neck cancer, salivary gland cancer and gastrointestinal stromal tumor (GIST); wherein the throat cancer is preferably nasopharyngeal carcinoma; the sarcoma is preferably osteosarcoma or Chondrosarcoma; the colorectal cancer is preferably colon cancer or rectal cancer; the fibroma is preferably neurofibroma.

本揭露中所述的淋巴瘤較佳為霍奇金氏疾病或非霍奇金淋巴瘤(例如套細胞淋巴瘤、彌漫性大B細胞淋巴瘤、濾泡中心淋巴瘤、邊緣區B細胞淋巴瘤、淋巴漿細胞淋巴瘤和外周T細胞淋巴瘤)；該肺癌較佳為非小細胞肺癌(NSCLC)(如肺腺癌、肺鱗狀細胞癌和大細胞癌等)或小細胞肺癌(SCLC)；該腎癌較佳選自腎細胞癌、透明細胞瘤和腎嗜酸細胞瘤；該白血病較佳為慢性白血病(例如慢性淋巴細胞白血病)或急性白血病(例如急性髓性白血病)。 The lymphoma described in this disclosure is preferably Hodgkin's disease or non-Hodgkin's lymphoma (such as mantle cell lymphoma, diffuse large B-cell lymphoma, follicle center lymphoma, marginal zone B-cell lymphoma) , lymphoplasmacytic lymphoma and peripheral T-cell lymphoma); the lung cancer is preferably non-small cell lung cancer (NSCLC) (such as lung adenocarcinoma, lung squamous cell carcinoma and large cell carcinoma, etc.) or small cell lung cancer (SCLC) The renal cancer is preferably selected from renal cell carcinoma, clear cell tumor and renal oncocytoma; the leukemia is preferably chronic leukemia (such as chronic lymphocytic leukemia) or acute leukemia (such as acute myeloid leukemia).

本揭露中所述的蛋白激酶較佳為受體酪胺酸激酶(RTKs)；較佳地，受體酪胺酸激酶(RTKs)為TAM、MET、KDR或它們的組合。 The protein kinases described in this disclosure are preferably receptor tyrosine kinases (RTKs); preferably, the receptor tyrosine kinases (RTKs) are TAM, MET, KDR or a combination thereof.

本揭露中所述的蛋白激酶為受體酪胺酸激酶(RTKs)；較佳地，受體酪胺酸激酶(RTKs)為Axl、Mer、TYRO3、MET、KDR或它們的組合。 The protein kinases described in this disclosure are receptor tyrosine kinases (RTKs); preferably, the receptor tyrosine kinases (RTKs) are Axl, Mer, TYRO3, MET, KDR or combinations thereof.

可將活性化合物製成適合於藉由任何適當途徑給藥的形式，藉由常規方法使用一種或多種藥學上可接受的載體來配製本揭露的組成物。因此，本揭露的活性化合物可以配製成用於口服給藥、注射(例如靜脈內、肌肉內或皮下)給藥，吸入或吹入給藥的各種劑型。本揭露的化合物也可以配製成例如片劑、硬或軟膠囊、水性或油性混懸液、乳劑、注射液、可分散性粉末或顆粒、栓劑、錠劑或糖漿等劑型。 The active compounds may be prepared in a form suitable for administration by any suitable route, and the compositions of the present disclosure may be formulated by conventional methods using one or more pharmaceutically acceptable carriers. Accordingly, the active compounds of the present disclosure may be formulated in various dosage forms for oral administration, injection (eg, intravenous, intramuscular or subcutaneous), administration by inhalation or insufflation. The compounds of the present disclosure can also be formulated into dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges or syrups.

作為一般性指導，活性化合物較佳是以單位劑量的方式，或者是以患者可以以單劑自我給藥的方式。本揭露化合物或組合物的單位劑量的表達方式可以是片劑、膠囊、扁囊劑、瓶裝藥水、藥粉、顆粒劑、錠劑、栓劑、再生藥粉或液體製劑。合適的單位劑量可以是0.1~1000mg。 As a general guide, the active compound is preferably presented in unit dosage form, or in such a form that the patient can self-administer as a single dose. The unit dosage form of a compound or composition of the present disclosure may be expressed as a tablet, capsule, cachet, bottled solution, powder, granule, lozenge, suppository, reconstitution powder or liquid preparation. A suitable unit dose may be 0.1 to 1000 mg.

本揭露的醫藥組成物除活性化合物外，可含有一種或多種輔料，該輔料選自以下成分：填充劑(稀釋劑)、黏合劑、潤濕劑、崩解劑或賦形劑等。根據給藥方法的不同，組成物可含有0.1至99重量%的活性化合物。 In addition to the active compound, the pharmaceutical composition of the present disclosure may contain one or more excipients selected from the following components: fillers (diluents), binders, wetting agents, disintegrants or excipients. Depending on the method of administration, the compositions may contain from 0.1 to 99% by weight of active compound.

片劑含有活性成分和用於混合的適宜製備片劑的無毒的可藥用的賦形劑。這些賦形劑可以是惰性賦形劑、造粒劑、崩解劑、黏合劑和潤滑劑。這些片劑可以不包衣或可藉由掩蓋藥物的味道或在胃腸道中延遲崩解和吸收，因而在較長時間內提供緩釋作用的已知技術將其包衣。 Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrants, binders and lubricants. These tablets may be uncoated or coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over a longer period of time.

也可用其中活性成分與惰性固體稀釋劑或其中活性成分與水溶性載體或油溶媒混合的軟明膠膠囊提供口服製劑。 Oral formulations can also be provided in soft gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent, or where the active ingredient is mixed with a water-soluble carrier or an oil vehicle.

水混懸液含有活性物質和用於混合的適宜製備水混懸液的賦形劑。此類賦形劑是懸浮劑、分散劑或濕潤劑。水混懸液也可以含有一種或多種防腐劑、一種或多種著色劑、一種或多種矯味劑和一種或多種甜味劑。 Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. Aqueous suspensions may also contain a or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweeteners.

油混懸液可藉由使活性成分懸浮於植物油，或礦物油配製而成。油懸浮液可含有增稠劑。可加入上述的甜味劑和矯味劑，以提供可口的製劑。可藉由加入抗氧化劑保存這些組成物。 Oily suspensions can be formulated by suspending the active ingredient in a vegetable or mineral oil. The oily suspensions may contain a thickening agent. Sweetening and flavoring agents as mentioned above may be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.

本揭露的醫藥組成物也可以是水包油乳劑的形式。油相可以是植物油，或礦物油或其混合物。適宜的乳化劑可以是天然產生的磷脂，乳劑也可以含有甜味劑、矯味劑、防腐劑和抗氧劑。此類製劑也可含有緩和劑、防腐劑、著色劑和抗氧劑。 The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oily phase may be vegetable oil, or mineral oil or mixtures thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweetening agents, flavoring agents, preservatives and antioxidants. Such formulations may also contain a demulcent, a preservative, coloring agents and antioxidants.

本揭露的醫藥組成物可以是無菌注射水溶液形式。可以使用的可接受的溶媒或溶劑有水、林格氏液和等滲氯化鈉溶液。無菌注射製劑可以是其中活性成分溶於油相的無菌注射水包油微乳可藉由局部大量注射，將注射液或微乳注入患者的血流中。或者，最好按可保持本揭露化合物恆定循環濃度的方式給予溶液和微乳。為保持這種恆定濃度，可使用連續靜脈內遞藥裝置。這種裝置的實例是Deltec CADD-PLUS.TM.5400型靜脈注射泵。 The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous solutions. Among the acceptable vehicles or solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation can be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oily phase. The injection or microemulsion can be injected into the patient's bloodstream by local bolus injection. Alternatively, solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the disclosed compounds. To maintain this constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS.TM. Model 5400 IV pump.

本揭露的醫藥組成物可以是用於肌內和皮下給藥的無菌注射水或油混懸液的形式。可按已知技術，用適宜的分散劑或濕潤劑和懸浮劑配製該混懸液。無菌注射製劑也可以是在腸胃外可接受的無毒稀釋劑或溶劑中製備的無菌注射溶液或混懸液。此外，可方便地用無菌固定油作為溶劑或懸浮介質。為此目的，可使用任何調和固定油。此外，脂肪酸也可以製備注射劑。 The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration. This suspension may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent. In addition, sterile fixed oils are conveniently employed as a solvent or suspending medium. For this purpose, any blended and fixed oil may be used. In addition, fatty acids are also used in the preparation of injectables.

可按用於直腸給藥的栓劑形式給予本揭露化合物。可藉由將藥物與在普通溫度下為固體但在直腸中為液體，因而在直腸中會溶化而釋放藥物的適宜的無刺激性賦形劑混合來製備這些醫藥組成物。 Compounds of the disclosure may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.

可藉由加入水來製備水混懸的可分散粉末和顆粒給予本揭露化合物。可藉由將活性成分與分散劑或濕潤劑、懸浮劑或一種或多種防腐劑混合來製備這些醫藥組成物。 Aqueous suspensions of dispersible powders and granules can be prepared by the addition of water to administer the disclosed compounds. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives.

如所屬技術領域具有通常知識者所熟知的，藥物的給藥劑量依賴於多種因素，包括但並非限定於以下因素：所用具體化合物的活性、患者的年齡、患者的體重、患者的健康狀況、患者的行為、患者的飲食、給藥時間、給藥方式、***的速率、藥物的組合、疾病的嚴重性等；另外，最佳的治療方式如治療的模式、化合物的日用量或可藥用的鹽的種類可以根據傳統的治療方案來驗證。 As is well known to those of ordinary skill in the art, the dosage of a drug to be administered depends on a variety of factors including, but not limited to, the activity of the particular compound used, the age of the patient, the weight of the patient, the state of the patient's health, the patient's behavior, patient’s diet, administration time, administration method, excretion rate, drug combination, disease severity, etc.; in addition, the optimal treatment method such as the mode of treatment, the daily dosage of the compound or the pharmaceutically acceptable The type of salt can be verified according to the traditional treatment plan.

術語說明 Glossary

除非有相反陳述，在說明書和申請專利範圍中使用的術語具有下述含義。 Unless stated otherwise, the terms used in the specification and claims have the following meanings.

術語“烷基”指飽和的直鏈或支鏈脂肪族烴基，其具有1至20個碳原子(即C_1-20烷基)。該烷基較佳具有1至12個(例如1、2、3、4、5、6、7、8、9、10、11和12個)碳原子的烷基(即C_1-12烷基)，更佳具有1至6個碳原子的烷基(即C_1-6烷基)。非限制性實例包括甲基、乙基、正丙基、異丙基、正丁基、異丁基、第三丁基、第二丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1- 二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各種支鏈異構體等。最佳具有1至6個碳原子的低級烷基，非限制性實施例包括甲基、乙基、正丙基、異丙基、正丁基、異丁基、第三丁基、第二丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的，當被取代時，其可以在任何可使用的連接點上被取代，取代基較佳選自D原子、鹵素、烷氧基、鹵烷基、鹵烷氧基、環烷基氧基、雜環基氧基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基、雜芳基中的一個或多個。 The term "alkyl" refers to a saturated linear or branched aliphatic hydrocarbon group having 1 to 20 carbon atoms (ie, C _1-20 alkyl). The alkyl group is preferably an alkyl group having 1 to 12 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (ie C _1-12 alkyl ), more preferably an alkyl group having 1 to 6 carbon atoms (ie C _1-6 alkyl). Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, second-butyl, n-pentyl, 1,1-dimethylpropyl , 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl- 2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1 ,3-Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl , 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-di Methylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl , 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4 -Ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3 -Ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. Preferably lower alkyl having 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, second-butyl Base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl group, 2,3-dimethylbutyl group, etc. Alkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, substituents are preferably selected from D atoms, halogen, alkoxy, haloalkyl, haloalkane One or more of oxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl .

術語“亞(伸)烷基”指二價烷基，其中烷基如上所定義，其具有1至20個(例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20個)碳原子(即C_1-20亞(伸)烷基)。該亞(伸)烷基較佳具有1至12個(例如1、2、3、4、5、6、7、8、9、10、11和12個) 碳原子(即C_1-12亞(伸)烷基)，更佳具有1至6個碳原子(即C_1-6亞(伸)烷基)。亞(伸)烷基的非限制性實例包括但不限於亞甲基(-CH₂-)、1,1-亞乙基(-CH(CH₃)-)、1,2-伸乙基(-CH₂CH₂)-、1,1-亞丙基(-CH(CH₂CH₃)-)、1,2-伸丙基(-CH₂CH(CH₃)-)、1,3-伸丙基(-CH₂CH₂CH₂-)、1,4-伸丁基(-CH₂CH₂CH₂CH₂-)等。亞(伸)烷基可以是取代的或非取代的，當被取代時，其可以在任何可使用的連接點上被取代，取代基較佳選自烯基、炔基、烷氧基、鹵烷氧基、環烷基氧基、雜環基氧基、烷硫基、烷基胺基、鹵素、巰基、羥基、硝基、氰基、環烷基、雜環基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基和側氧中的一個或多個。 The term "(alkylene)" refers to a divalent alkyl group, wherein the alkyl group is as defined above, which has 1 to 20 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie C _1-20 alkylene). The (alkylene)alkylene preferably has 1 to 12 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (ie C _1-12 (alkylene)), more preferably having 1 to 6 carbon atoms (ie C _1-6 (alkylene)). Non-limiting examples of alkylene include, but are not limited to, methylene ( _-CH2- ), 1,1-ethylene (-CH( _CH3 )-), 1,2-ethylene ( -CH ₂ CH ₂ )-, 1,1-propylene (-CH(CH ₂ CH ₃ )-), 1,2-propylidene (-CH ₂ CH(CH ₃ )-), 1,3- Propylene (-CH ₂ CH ₂ CH ₂ -), 1,4-butylene (-CH ₂ CH ₂ CH ₂ CH ₂ -), etc. Alkylene may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably the substituent is selected from alkenyl, alkynyl, alkoxy, halo Alkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl One or more of group, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and pendant oxygen.

術語“烯基”指分子中含有至少一個碳碳雙鍵的烷基，其中烷基的定義如上所述，其具有2至12個(例如2、3、4、5、6、7、8、9、10、11和12個)碳原子的烯基(即C_2-12烯基)。該烯基較佳具有2至6個碳原子的烯基(即C_2-6烯基)。非限制性的實例包括：乙烯基、丙烯基、異丙烯基、丁烯基等。烯基可以是取代的或非取代的，當被取代時，其較佳選自烷氧基、鹵素、鹵烷基、鹵烷氧基、環烷基氧基、雜環基氧基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基和雜芳基中的一個或多個。 The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein the definition of the alkyl group is as described above, and it has 2 to 12 (such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (ie C _2-12 alkenyl). The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (ie, a C _2-6 alkenyl group). Non-limiting examples include: vinyl, propenyl, isopropenyl, butenyl, and the like. Alkenyl may be substituted or unsubstituted, and when substituted, it is preferably selected from alkoxy, halo, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, One or more of hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

術語“炔基”指分子中含有至少一個碳碳三鍵的烷基，其中烷基的定義如上所述，其具有2至12個(例如2、3、4、5、6、7、8、9、10、11和12個)碳原子(即C_2-12炔基)。該炔基較佳具有2至6個碳原子(即C_2-6炔基)。炔基可以是取代的或非取代的，當被取代時，其較佳選自烷氧基、鹵素、鹵烷基、鹵烷氧基、環烷基氧基、雜環基氧基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基和雜芳基中的一個或多個。 The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein the definition of the alkyl group is as described above, and it has 2 to 12 (such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (ie C _2-12 alkynyl). The alkynyl group preferably has 2 to 6 carbon atoms (ie C _2-6 alkynyl). Alkynyl may be substituted or unsubstituted, and when substituted, it is preferably selected from alkoxy, halo, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, One or more of hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

術語“烷氧基”指-O-(烷基)，其中烷基的定義如上所述。非限制性的實例包括：甲氧基、乙氧基、丙氧基和丁氧基等。烷氧基可以是取代的或非取代的，當被取代時，其可以在任何可使用的連接點被取代，取代基較佳選自氘原子、鹵素、烷氧基、鹵烷基、鹵烷氧基、環烷基氧基、雜環基氧基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基和雜芳基中的一個或多個。 The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples include: methoxy, ethoxy, propoxy, and butoxy, and the like. Alkoxy may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, substituents are preferably selected from deuterium atoms, halogen, alkoxy, haloalkyl, haloalkane One or more of oxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl .

術語“環烷基”指飽和或部分不飽和的單環或多環環狀烴取代基，環烷基環具有3至20個(例如3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20個)碳原子(即3至20員環烷基)，較佳具有3至14個(例如3、4、5、6、7、8、9、10、11、12、13和14個)碳原子(即3至14員環烷基)，更佳具有3至8個碳原子(即3至8員環烷基)，進一步佳具有3至6個碳原子(即3至6員環烷基)，最佳具有5或6個碳原子(即5至6員環烷基)。單環環烷基的非限制性實例包括環丙基、環丁基、環戊基、環戊烯基、環己基、環己烯基、環己二烯基、環庚基、環庚三烯基和環辛基等；多環環烷基包括螺環烷基、稠環烷基和橋環烷基。 The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent having 3 to 20 (e.g. 3, 4, 5, 6, 7, 8, 9, 10 , 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie 3 to 20 membered cycloalkyl), preferably with 3 to 14 (eg 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14) carbon atoms (ie 3 to 14 membered cycloalkyl), more preferably 3 to 8 carbon atoms (ie 3 to 8 membered cycloalkyl ), further preferably has 3 to 6 carbon atoms (ie 3 to 6 membered cycloalkyl), most preferably has 5 or 6 carbon atoms (ie 5 to 6 membered cycloalkyl). Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Base and cyclooctyl, etc.; polycyclic cycloalkyl includes spirocycloalkyl, fused cycloalkyl and bridged cycloalkyl.

術語“螺環烷基”指5至20員，單環之間共用一個碳原子(稱螺原子)的多環基團，其可以含有一個或多個雙鍵。較佳6至14員，更佳7至10員(例如7、8、9或10員)。根據環與環之間共用螺原子的數目將螺環烷基分為單螺環烷基或多螺環烷基(如雙螺環烷基)，較佳為單螺環烷基或雙螺環烷基。更佳為3員/5員、3員/6員、4員/4員、4員/5員、4員/6員、5員/5員、5員/6員或6員/6員單螺環烷基。螺環烷基的非限制性實例包括： The term "spirocycloalkyl" refers to a polycyclic group with 5 to 20 members that shares one carbon atom (called a spiro atom) between monocyclic rings, which may contain one or more double bonds. Preferably 6 to 14 members, more preferably 7 to 10 members (eg 7, 8, 9 or 10 members). According to the number of spiro atoms shared between the ring and the ring, the spirocycloalkyl group is divided into a single spirocycloalkyl group or a multi-spirocycloalkyl group (such as a double spirocycloalkyl group), preferably a single spirocycloalkyl group. Cycloalkyl or double spirocycloalkyl. More preferably 3/5 members, 3/6 members, 4/4 members, 4/5 members, 4/6 members, 5/5 members, 5/6 members or 6/6 members Single spirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

術語“稠環烷基”指5至20員，系統中的每個環與體系中的其他環共享毗鄰的一對碳原子的全碳多環基團，其中一個或多個環可以含有一個或多個雙鍵。較佳為6至14員，更佳為7至10員(例如7、8、9或10員)。根據組成環的數目可以分為雙環、三環、四環等多環稠環烷基，較佳為雙環或三環稠環烷基，更佳為3員/4員、3員/5員、3員/6員、4員/4員、4員/5員、4員/6員、5員/3員、5員/4員、5員/5員、5員/6員、6員/3員、6員/4員、6員/5員、6員/6員、6員/7員、7員/5員或7員/6員雙環烷基。稠環烷基的非限制性實例包括： The term "fused cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, each ring of which shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or multiple double bonds. Preferably it is 6 to 14 members, more preferably 7 to 10 members (eg 7, 8, 9 or 10 members). According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic and other polycyclic fused cycloalkyl groups, preferably bicyclic or tricyclic fused cycloalkyl groups, more preferably 3-membered/4-membered, 3-membered/5-membered, 3 people/6 people, 4 people/4 people, 4 people/5 people, 4 people/6 people, 5 people/3 people, 5 people/4 people, 5 people/5 people, 5 people/6 people, 6 people /3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered bicycloalkyl. Non-limiting examples of fused cycloalkyl groups include:

術語“橋環烷基”指5至20員，任意兩個環共用兩個不直接連接的碳原子的全碳多環基團，其可以含有一個或多個雙鍵。較佳為6至14員，更佳為7至10員(例如7、8、9或10員)。根據組成環的數目可以分為雙環、三環、四環或多環橋環烷基，較佳為雙環、三環或四環橋環烷基，更佳為雙環或三環橋環烷基。橋環烷基的非限制性實例包括： The term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms not directly attached, which may contain one or more double bonds. Preferably it is 6 to 14 members, more preferably 7 to 10 members (eg 7, 8, 9 or 10 members). According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic bridged cycloalkyl, more preferably bicyclic or tricyclic bridged cycloalkyl. Non-limiting examples of bridged cycloalkyl groups include:

該環烷基環包括如上所述的環烷基(包括單環、螺環、稠環和橋環)稠合於芳基、雜芳基或雜環烷基環上，其中與母體結構連接在一起的環為環烷基，非限制性實例包括

、

和

等；較佳

和

。 The cycloalkyl ring includes a cycloalkyl group as described above (including monocyclic, spiro, fused and bridged rings) fused to an aryl, heteroaryl or heterocycloalkyl ring wherein the bond to the parent structure is at The rings together are cycloalkyl, non-limiting examples include

,

with

etc; better

with

.

環烷基可以是取代的或非取代的，當被取代時，其可以在任何可使用的連接點上被取代，取代基較佳選自鹵素、烷基、烷氧基、鹵烷基、鹵烷氧基、環烷基氧基、雜環基氧基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基、雜芳基中的一個或多個。 Cycloalkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, halo One or more of alkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl indivual.

術語“雜環基”指飽和或部分不飽和單環或多環環狀取代基，其具有3至20個環原子，其中一個或多個環原子為選自氮、氧和硫的雜原子，該硫可視需要被氧化(即形成亞碸或碸)，其餘環原子為碳。較佳具有3至14個(例如3、4、5、6、7、8、9、10、11、12、13和14個)環原子，其中1~4個(例如1、2、3和4個)是雜原子(即3至14員雜環基)；更佳具有3至8個(例如3、4、5、6、7和8個)環原子，其中1-3個(例如1、2和3個)是雜原子(即3至8員雜環基)或6至14個環原子(例如6、7、8、9、10、11、12、13和14個)，其中1-3個(例如1、2和3個)是雜原子(即6至14員雜環基)；更佳具有3至6個環原子，其中1-3個(例如1、2和3個)是雜原子(即3至6員雜環基)；最佳包含5或6個環原子，其中1-3個是雜原子(即5至6員雜環基)。單環雜環基的非限制性實例包括吡咯烷基、四氫吡喃基、1,2,3,6-四氫吡啶基、哌啶基、哌嗪基、嗎啉基、硫嗎啉基、高哌嗪基等。多環雜環基包括螺雜環基、稠雜環基和橋雜環基。 The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic ring substituent having 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen and sulfur, The sulfur can be optionally oxidized (ie to form argon or sulfur) and the remaining ring atoms are carbon. Preferably having 3 to 14 (for example 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14) ring atoms, wherein 1 to 4 (for example 1, 2, 3 and 4) are heteroatoms (ie 3 to 14 membered heterocyclyl); more preferably 3 to 8 (eg 3, 4, 5, 6, 7 and 8) ring atoms, of which 1-3 (eg 1 , 2 and 3) are heteroatoms (ie 3 to 8 membered heterocyclyl) or 6 to 14 ring atoms (eg 6, 7, 8, 9, 10, 11, 12, 13 and 14), wherein 1 - 3 (eg 1, 2 and 3) are heteroatoms (ie 6 to 14 membered heterocyclyl); more preferably have 3 to 6 ring atoms sub, wherein 1-3 (eg 1, 2 and 3) are heteroatoms (ie 3 to 6 membered heterocyclyl); optimally contain 5 or 6 ring atoms, of which 1-3 are heteroatoms (ie 5 to 6 membered heterocyclyl). Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl , Homopiperazinyl, etc. Polycyclic heterocyclyls include spiroheterocyclyls, fused heterocyclyls and bridged heterocyclyls.

術語“螺雜環基”指5至20員，單環之間共用一個原子(稱螺原子)的多環雜環基團，其中一個或多個環原子為選自氮、氧和硫的雜原子，該硫可視需要被氧化(即形成亞碸或碸)，其餘環原子為碳。其可以含有一個或多個雙鍵。較佳6至14員(例如6、7、8、9、10、11、12、13和14員)，更佳7至10員(例如7、8、9或10員)。根據環與環之間共用螺原子的數目將螺雜環基分為單螺雜環基或多螺雜環基(如雙螺雜環基)，較佳為單螺雜環基或雙螺雜環基。最較佳為3員/5員、3員/6員、4員/4員、4員/5員、4員/6員、5員/5員、5員/6員或6員/6員單螺雜環基。螺雜環基的非限制性實例包括： The term "spiroheterocyclyl" refers to a multi-ring heterocyclic group with 5 to 20 members sharing one atom (called spiro atom) between monocyclic rings, wherein one or more ring atoms are heterocyclic groups selected from nitrogen, oxygen and sulfur atoms, the sulfur can be oxidized (ie to form argon or sulfur) if desired, and the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably 6 to 14 members (eg 6, 7, 8, 9, 10, 11, 12, 13 and 14 members), more preferably 7 to 10 members (eg 7, 8, 9 or 10 members). According to the number of spiro atoms shared between the ring and the ring, the spiroheterocyclyl is divided into a single spiroheterocyclyl or a polyspiroheterocyclyl (such as a double spiroheterocyclyl), preferably a single spiroheterocyclyl or a double spiroheterocyclyl Ring base. Most preferably 3/5, 3/6, 4/4, 4/5, 4/6, 5/5, 5/6 or 6/6 member monospiroheterocyclyl. Non-limiting examples of spiroheterocyclyls include:

術語“稠雜環基”指5至20員，系統中的每個環與體系中的其他環共享毗鄰的一對原子的多環雜環基團，一個或多個環可以含有一個或多個雙鍵，其中一個或多個環原子為選自氮、氧和硫的雜原子，該硫可視需要被氧化(即形成亞碸或碸)，其餘環原子為碳。較佳6至14員(例如6、7、8、9、10、11、12、13和14員)，更佳7至10員(例如7、8、9 或10員)。根據組成環的數目可以分為雙環、三環、四環等多環稠雜環基，較佳為雙環或三環稠雜環基，更佳為3員/4員、3員/5員、3員/6員、4員/4員、4員/5員、4員/6員、5員/3員、5員/4員、5員/5員、5員/6員、6員/3員、6員/4員、6員/5員、6員/6員、6員/7員、7員/5員或7員/6員雙環稠雜環基。稠雜環基的非限制性實例包括： The term "fused heterocyclyl" refers to 5 to 20 membered polycyclic heterocyclic groups in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more Double bonds in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, the sulfur being optionally oxidized (ie to form argon or thionium), and the remaining ring atoms being carbon. Preferably 6 to 14 members (such as 6, 7, 8, 9, 10, 11, 12, 13 and 14 members), more preferably 7 to 10 members (such as 7, 8, 9 or 10 members). According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic and other polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic fused heterocyclic groups, more preferably 3-membered/4-membered, 3-membered/5-membered, 3 people/6 people, 4 people/4 people, 4 people/5 people, 4 people/6 people, 5 people/3 people, 5 people/4 people, 5 people/5 people, 5 people/6 people, 6 people /3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered bicyclic fused heterocyclyl. Non-limiting examples of fused heterocyclic groups include:

術語“橋雜環基”指5至20員，任意兩個環共用兩個不直接連接的原子的多環雜環基團，其可以含有一個或多個雙鍵，其中一個或多個環原子為選自氮、氧和硫的雜原子，該硫可視需要被氧化(即形成亞碸或碸)，其餘環原子為碳。較佳6至14員(例如6、7、8、9、10、11、12、13和14員)，更佳7至10員(例如7、8、9或10員)。根據組成環的數目可以分為雙環、三環、四環等多環橋雜環基，較佳為雙環、三環或四環，更佳為雙環或三環橋雜環基。橋雜環基的非限制性實例包括： The term "bridged heterocyclyl" refers to a 5 to 20-membered polycyclic heterocyclic group in which any two rings share two atoms not directly connected, which may contain one or more double bonds, in which one or more ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, the sulfur optionally being oxidized (ie to form argon or argon), and the remaining ring atoms being carbon. Preferably 6 to 14 members (eg 6, 7, 8, 9, 10, 11, 12, 13 and 14 members), more preferably 7 to 10 members (eg 7, 8, 9 or 10 members). According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic and other polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic bridged heterocyclic groups. Non-limiting examples of bridged heterocyclyl groups include:

該雜環基環包括如上所述的雜環基(包括單環、螺雜環、稠雜環和橋雜環)稠合於芳基、雜芳基或環烷基環上，其中與母體結構連接在一起的環為雜環基，其非限制性實例包括： The heterocyclyl ring includes a heterocyclyl as described above (including monocyclic, spiroheterocycle, fused heterocycle and bridged heterocycle) fused to an aryl, heteroaryl or cycloalkyl ring wherein the parent structure The rings joined together are heterocyclyl, non-limiting examples of which include:

和

等。

with

Wait.

雜環基可以是取代的或非取代的，當被取代時，其可以在任何可使用的連接點上被取代，取代基較佳選自鹵素、烷基、烷氧基、鹵烷基、鹵烷氧基、環烷基氧基、雜環基氧基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基和雜芳基中的一個或多個。 The heterocyclyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, halo One or more of alkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl indivual.

術語“芳基”指具有共軛的π電子體系的6至14員全碳單環或稠合多環(稠合多環是共享毗鄰碳原子對的環)基團，較佳6至10員，例如苯基和萘基。該芳基環包括如上所述的芳基環稠合於雜芳基、雜環基或環烷基環上，其中與母體結構連接在一起的環為芳基環，其非限制性實例包括： The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (a fused polycyclic is a ring that shares adjacent pairs of carbon atoms) group, preferably 6 to 10 membered, having a conjugated π-electron system. , such as phenyl and naphthyl. The aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclyl or cycloalkyl ring wherein the ring bonded to the parent structure is an aryl ring, non-limiting examples of which include:

芳基可以是取代的或非取代的，當被取代時，其可以在任何可使用的連接點上被取代，取代基較佳選自鹵素、烷基、烷氧基、鹵烷基、鹵烷氧基、環烷基氧基、雜環基氧基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基和雜芳基中的一個或多個。 Aryl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, substituents are preferably selected from halogen, alkyl, alkoxy, haloalkane In radical, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl one or more.

術語“雜芳基”指包含1至4個雜原子(例如1、2、3和4個)、5至14個環原子的雜芳族體系，其中雜原子選自氧、硫和氮。雜芳基較佳為5至10員(例如5、6、7、8、9或10員)，更佳為5員或6員(即5至6員雜芳基)，例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、噠嗪基、咪唑基、吡唑基、***基、四唑基等。該雜芳基環包括如上述的雜芳基稠合於芳基、雜環基或環烷基環上，其中與母體結構連接在一起的環為雜芳基環，其非限制性實例包括： The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms (eg 1, 2, 3 and 4), 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 membered (eg 5, 6, 7, 8, 9 or 10 membered), more preferably 5 or 6 membered (ie 5 to 6 membered heteroaryl), eg furyl, thiophene Base, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring includes a heteroaryl as described above fused to an aryl, heterocyclyl or cycloalkyl ring wherein the ring bonded to the parent structure is a heteroaryl ring, non-limiting examples of which include:

雜芳基可以是取代的或非取代的，當被取代時，其可以在任何可使用的連接點上被取代，取代基較佳選自鹵素、烷基、烷氧基、鹵烷基、鹵烷氧基、環烷基氧基、雜環基氧基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基和雜芳基中的一個或多個。 Heteroaryl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, halo One or more of alkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl indivual.

上述環烷基、雜環基、芳基和雜芳基包括從母體環原子上除去一個氫原子所衍生的殘基，或從母體的相同環原子或兩個不同的環原子上除去兩個氫原子所衍生的殘基即“亞(伸)環烷基”、“亞(伸)雜環基”、“亞(伸)芳基”、“亞(伸)雜芳基”。 The above cycloalkyl, heterocyclyl, aryl and heteroaryl groups include residues derived from a parent ring atom by removing a hydrogen atom, or from the same parent ring atom or two different ring atoms Residues derived by removing two hydrogen atoms from above are "(extended) cycloalkylene", "(extended) heterocyclyl", "(extended) aryl", "(extended) heteroaryl" .

術語“胺基保護基”是為了使分子其它部位進行反應時胺基保持不變，在胺基上引入的易於脫去的基團對胺基進行保護。非限制性實施例包含(三甲基矽)乙氧基甲基、四氫吡喃基、第三丁氧羰基(Boc)、乙醯基、苄基、苄氧羰基(Cbz)、烯丙基和對甲氧苄基等。這些基團可視需要地被選自鹵素、烷氧基或硝基中的1-3個取代基所取代。 The term "amino group protecting group" is used to protect the amine group by the easy-to-remove group introduced on the amine group to keep the amine group unchanged when other parts of the molecule react. Non-limiting examples include (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butoxycarbonyl (Boc), acetyl, benzyl, benzyloxycarbonyl (Cbz), allyl and p-methoxybenzyl et al. These groups may be optionally substituted with 1 to 3 substituents selected from halogen, alkoxy or nitro.

術語“羥基保護基”是指通常用於阻斷或保護羥基而反應在化合物的其它官能團上進行的羥基衍生物。非限制性的實例包括：三甲基矽基(TMS)、三乙基矽基(TES)、三異丙基矽基(TIPS)、第三丁基二甲基矽烷基(TBS)、第三丁基二苯基矽基、甲基、第三丁基、烯丙基、苄基、甲氧基甲基(MOM)、乙氧基乙基、2-四氫吡喃基(THP)、甲醯基、乙醯基、苯甲醯基、對硝基苯甲醯基等。 The term "hydroxyl protecting group" refers to a hydroxy derivative that is usually used to block or protect a hydroxy group to react on other functional groups of the compound. Non-limiting examples include: trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tertiarybutyldimethylsilyl (TBS), tertiary Butyldiphenylsilyl, methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), methyl Acyl, acetyl, benzoyl, p-nitrobenzoyl, etc.

術語“環烷基氧基”指環烷基-O-，其中環烷基如上所定義。 The term "cycloalkyloxy" refers to cycloalkyl-O-, wherein cycloalkyl is as defined above.

術語“雜環基氧基”指雜環基-O-，其中雜環基如上所定義。 The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.

術語“烷硫基”指烷基-S-，其中烷基如上所定義。 The term "alkylthio" refers to alkyl-S-, wherein alkyl is as defined above.

術語“鹵烷基”指烷基被一個或多個鹵素取代，其中烷基如上所定義。 The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

術語“鹵烷氧基”指烷氧基被一個或多個鹵素取代，其中烷氧基如上所定義。 The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy group is as defined above.

術語“氘代烷基”指烷基被一個或多個氘原子取代，其中烷基如上所定義。 The term "deuteroalkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

術語“羥烷基”指烷基被一個或多個羥基取代，其中烷基如上所定義。 The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

術語“鹵素”指氟、氯、溴或碘。 The term "halogen" refers to fluorine, chlorine, bromine or iodine.

術語“羥基”指-OH。 The term "hydroxyl" refers to -OH.

術語“巰基”指-SH。 The term "mercapto" refers to -SH.

術語“胺基”指-NH₂。 The term "amino" refers to _-NH2 .

術語“氰基”指-CN。 The term "cyano" refers to -CN.

術語“硝基”指-NO₂。 The term "nitro" refers to _-NO2 .

術語“側氧”指“=O”。 The term "side oxygen" refers to "=0".

術語“羰基”指C=O。 The term "carbonyl" refers to C=O.

術語“羧基”指-C(O)OH。 The term "carboxy" refers to -C(O)OH.

術語“羧酸酯基”指-C(O)O(烷基)、-C(O)O(環烷基)、(烷基)C(O)O-或(環烷基)C(O)O-，其中烷基和環烷基如上所定義。 The term "carboxylate" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O )O-, wherein alkyl and cycloalkyl are as defined above.

本揭露的化合物包含其同位素衍生物。術語“同位素衍生物”指結構不同僅在於存在一種或多種同位素富集原子的化合物。例如，具有本揭露的結構，用“氘”或“氚”代替氫，或者用¹⁸F-氟標記(¹⁸F同位素)代替氟，或者用¹¹C-，¹³C-，或者¹⁴C-富集的碳(¹¹C-，¹³C-，或者¹⁴C-碳標記；¹¹C-，¹³C-，或者¹⁴C-同位素)代替碳原子的化合物處於本揭露的範圍內。這樣的化合物可用作例如生物學測定中的分析工具或探針，或者可以用作疾病的體內診斷成像示蹤劑，或者作為藥效學、藥動學或受體研究的示蹤劑。本揭露的各種氘化形式的化合物是指與碳原子連接的各個可用的氫原子可獨立地被氘原子替換。所屬技術領域具有通常知識者能夠參考相關文獻合成氘化形式的化合物。在製備氘代形式的化合物時可使用市售的氘代起始物質，或它們可使用常規技術採用氘代試劑合成，氘代試劑包括但不限於氘代硼烷、三氘代硼烷四氫呋喃溶液、氘代氫化鋰鋁、氘代碘乙烷和氘代碘甲烷等。氘代物通常可以保留與未氘代的化合物相當的活性，並且當氘代在某些特定位點時可以取得更好的代謝穩定性，從而獲得某些治療優勢。 Compounds of the present disclosure include isotopic derivatives thereof. The term "isotopically derivative" refers to compounds that differ in structure only by the presence of one or more isotopically enriched atoms. For example, with the structure of the present disclosure, hydrogen is replaced by "deuterium" or "tritium", or fluorine is replaced by ¹⁸ F-fluorine label ( ¹⁸ F isotope), or ¹¹ C-, ¹³ C-, or ¹⁴ C-enriched Compounds in which carbon atoms are replaced by carbon ( ¹¹ C-, ¹³ C-, or ¹⁴ C-carbon labels; ¹¹ C-, ¹³ C-, or ¹⁴ C-isotopes) are within the scope of the present disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays, or as tracers for in vivo diagnostic imaging of disease, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies. Various deuterated forms of compounds of the present disclosure mean that each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can refer to the relevant literature to synthesize the deuterated form of the compound. Commercially available deuterated starting materials can be used in the preparation of deuterated forms of the compounds, or they can be synthesized using conventional techniques using deuterated reagents including but not limited to deuterated borane, trideuterioborane in tetrahydrofuran , deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide, etc. Deuterated compounds generally retain comparable activity to undeuterated compounds, and can achieve better metabolic stability when deuterated at certain sites, thereby gaining certain therapeutic advantages.

本揭露化合物可以存在特定的立體異構體形式。術語“立體異構體”是指結構相同但原子在空間中的排列不同的異構體。其包括順式和反式(或Z和E)異構體、(-)-和(+)-異構體、(R)-和(S)-對映異構體、非對映異構體、(D)-和(L)-異構體、互變異構體、阻轉異構體、構象異構體及其混合物(如外消旋體、非對映異構體的混合物)。本揭露化合物中的取代基可以存在另外的不對稱原子。所有這些立體異構體以及它們的混合物，均包括在本揭露的範圍內。可以藉由手性合成、手性試劑或者其他常規技術製備光學活性的(-)-和(+)-異構體、(R)-和(S)-對映異構體以及(D)-和(L)-異構體。本揭露某化合物的一種異構體，可以藉由不對稱合成或者手性助劑來製備，或者，當分子中含有鹼性官能團(如胺基)或酸性官能團(如羧基)時，與適當的光學活性的酸或鹼形成非對映異構體的鹽，然後藉由本領域所公知的常規方法進行非對映異構體拆分，得到純的異構體。此外，對映異構體和非對映異構體的分離通常是藉由色譜法完成。 Compounds of the present disclosure may exist in certain stereoisomeric forms. The term "stereoisomer" refers to isomers that are identical in structure but differ in the arrangement of the atoms in space. It includes cis and trans (or Z and E ) isomers, (-)- and (+)-isomers, ( R )- and ( S )-enantiomers, diastereomers isomers, (D )- and ( L )-isomers, tautomers, atropisomers, conformers and mixtures thereof (eg racemates, mixtures of diastereomers). Substituents in compounds of the present disclosure may be present with additional asymmetric atoms. All such stereoisomers, as well as mixtures thereof, are included within the scope of the present disclosure. Optically active (-)- and (+)-isomers, ( R )- and ( S )-enantiomers and (D )- and ( L )-isomers. An isomer of a compound disclosed in this disclosure can be prepared by asymmetric synthesis or chiral auxiliary agents, or, when the molecule contains a basic functional group (such as an amine group) or an acidic functional group (such as a carboxyl group), it can be prepared with an appropriate Optically active acids or bases form diastereomeric salts, which are then resolved by conventional methods well known in the art to obtain the pure isomers. Furthermore, separation of enantiomers and diastereomers is usually accomplished by chromatography.

本揭露所述化合物的化學結構中，鍵“／”表示未指定構型，即如果化學結構中存在手性異構體，鍵“／”可以為“

”或“

”，或者同時包含“

”和“

”兩種構型。 In the chemical structure of the compound described in this disclosure, the bond "/" indicates that the configuration is not specified, that is, if there are chiral isomers in the chemical structure, the bond "/" can be "

"or"

, or both "

"with"

"Two configurations.

本揭露的化合物可以以不同的互變異構體形式存在，並且所有這樣的形式包含在本揭露的範圍內。術語“互變異構體”或“互變異構體形式”是指平衡存在並且容易從一種異構形式轉化為另一種異構形式的結構異構體。其包括所有可能的互變異構體，即以單一異構體的形式或以該互變異構體的任意比例的混合物的形式存在。非限制性的實例包括：酮-烯醇、亞胺-烯胺、內醯胺-內醯亞胺等。內醯胺-內醯亞胺平衡實例如下所示： The compounds of the present disclosure may exist in different tautomeric forms and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers that exist in equilibrium and are readily converted from one isomeric form to the other. It includes all possible tautomers, ie present as single isomers or as mixtures of such tautomers in any ratio. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactimine, and the like. An example of a lactam-lactimine equilibrium is shown below:

如當提及吡唑基時，應理解為包括如下兩種結構中的任何一種或兩種互變異構體的混合物： For example, when referring to pyrazolyl, it should be understood to include any one of the following two structures or a mixture of two tautomers:

所有的互變異構形式在本揭露的範圍內，且化合物的命名不排除任何互變異構體。 All tautomeric forms are within the scope of the disclosure, and the naming of compounds does not exclude any tautomers.

“視需要地”或“視需要”是指意味著隨後所描述的事件或環境可以但不必發生，該說明包括該事件或環境發生或不發生的場合。例如“視需要的被鹵素或者氰基取代的C_1-6烷基”是指鹵素或者氰基可以但不必須存在，該說明包括烷基被鹵素或者氰基取代的情形和烷基不被鹵素和氰基取代的情形。 "Optionally" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or does not occur. For example, "C _1-6 alkyl optionally substituted by halogen or cyano" means that halogen or cyano may but not necessarily exist, and this description includes the case where the alkyl is substituted by halogen or cyano and the alkyl is not substituted by halogen. And the case of cyano substitution.

“取代的”指基團中的一個或多個氫原子，較佳為1至6個，更佳為1至3個氫原子彼此獨立地被相應數目的取代基取代。所屬技術領域具有通常知識者能夠在不付出過多努力的情況下(藉由實驗或理論)確定可能或不可能的取代。例如，具有游離氫的胺基或羥基與具有不飽和(如烯屬)鍵的碳原子結合時可能是不穩定的。 "Substituted" means that one or more hydrogen atoms in a group, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms are independently substituted by the corresponding number of substituents. Those skilled in the art can determine (by experiment or theory) without undue effort Possible or impossible substitution. For example, an amine or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.

“醫藥組成物”表示含有一種或多種本文所述化合物或其生理學上/可藥用的鹽或前體藥物與其他化學組分的混合物，以及其他組分例如生理學/可藥用的載體和賦形劑。醫藥組成物的目的是促進對生物體的給藥，利於活性成分的吸收進而發揮生物活性。 "Pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof and other chemical components, and other components such as a physiologically/pharmaceutically acceptable carrier and excipients. The purpose of the pharmaceutical composition is to promote the administration to the living body, facilitate the absorption of the active ingredient and thus exert the biological activity.

“可藥用的鹽”是指本揭露化合物的鹽，可選自無機鹽或有機鹽。這類鹽用於哺乳動物體內時具有安全性和有效性，且具有應有的生物活性。可以在化合物的最終分離和純化過程中，或藉由使合適的基團與合適的鹼或酸反應來單獨製備鹽。通常用於形成藥學上可接受的鹽的鹼包括無機鹼，例如氫氧化鈉和氫氧化鉀，以及有機鹼，例如胺。通常用於形成藥學上可接受的鹽的酸包括無機酸以及有機酸。 "Pharmaceutically acceptable salt" refers to a salt of a compound of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals, and have proper biological activity. Salts can be prepared separately during the final isolation and purification of the compounds, or by reacting the appropriate group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as amines. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.

針對藥物或藥理學活性劑而言，術語“治療有效量”是指足以達到或至少部分達到預期效果的藥物或藥劑的用量。治療有效量的確定因人而異，取決於受體的年齡和一般情況，也取決於具體的活性物質，個案中合適的治療有效量可以由所屬技術領域具有通常知識者根據常規試驗確定。 With respect to a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to an amount of the drug or agent sufficient to achieve, or at least partially achieve, the desired effect. The determination of the therapeutically effective dose varies from person to person, depending on the age and general condition of the subject, and also depends on the specific active substance. The appropriate therapeutically effective dose in individual cases can be determined by those skilled in the art according to routine experiments.

本文所用的術語“藥學上可接受的”是指這些化合物、材料、組成物和/或劑型，在合理的醫學判斷範圍內，適用於與患者組織接觸而沒有過度毒性、刺激性、過敏反應或其他問題或併發症，具有合理的獲益/風險比，並且對預期的用途是有效。 As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms, which are suitable for use in contact with patient tissues without undue toxicity, irritation, allergic reaction or Other problems or complications that have a reasonable benefit/risk ratio and are valid for the intended use.

本文所使用的，單數形式的“一個”、“一種”和“該”包括複數引用，反之亦然，除非上下文另外明確指出。 As used herein, the singular forms "a", "an" and "the" include plural references and vice versa unless the context clearly dictates otherwise.

當將術語“約”應用於諸如pH、濃度、溫度等的參數時，表明該參數可以變化±10%，並且有時更佳地在±5%之內。如所屬技術領域具有通常知識者將理解的，當參數不是關鍵時，通常僅出於說明目的給出數字，而不是限制。 When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it means that the parameter may vary by ±10%, and sometimes preferably within ±5%. As will be understood by those of ordinary skill in the art, when a parameter is not critical, the numbers are generally given for illustrative purposes only, and not for limitation.

本揭露化合物的合成方法 The synthetic method of the disclosed compound

為了完成本揭露的目的，本揭露採用如下技術方案： In order to accomplish the purpose of this disclosure, this disclosure adopts the following technical solutions:

方案一 Option One

本揭露通式(I)所示的化合物，或其可藥用的鹽的製備方法，該方法包括： The present disclosure discloses a compound represented by general formula (I), or a preparation method of a pharmaceutically acceptable salt thereof, the method comprising:

通式(IA)的化合物或其鹽與通式(IB)的化合物或其鹽，在鹼性條件下，發生醯化反應，得到通式(I)的化合物或其可藥用的鹽， A compound of general formula (IA) or a salt thereof and a compound of general formula (IB) or a salt thereof, under alkaline conditions, undergo an acylation reaction to obtain a compound of general formula (I) or a pharmaceutically acceptable salt thereof,

其中， in,

X為鹵素；較佳為氯原子； X is a halogen; preferably a chlorine atom;

方案二 Option II

本揭露通式(II)所示的化合物，或其可藥用的鹽的製備方法，該方法包括： The present disclosure discloses a compound represented by general formula (II), or a preparation method of a pharmaceutically acceptable salt thereof, the method comprising:

通式(IIA)的化合物或其鹽與通式(IB)的化合物或其鹽，在鹼性條件下，發生醯化反應，得到通式(II)的化合物或其可藥用的鹽， A compound of general formula (IIA) or a salt thereof and a compound of general formula (IB) or a salt thereof, under alkaline conditions, undergo an acylation reaction to obtain a compound of general formula (II) or a pharmaceutically acceptable salt thereof,

其中， in,

X為鹵素；較佳為氯原子； X is a halogen; preferably a chlorine atom;

方案三 third solution

本揭露通式(III)所示的化合物，或其可藥用的鹽的製備方法，該方法包括： The present disclosure discloses a compound represented by general formula (III), or a preparation method of a pharmaceutically acceptable salt thereof, the method comprising:

通式(IIIA)的化合物或其鹽與通式(IB)的化合物或其鹽，在鹼性條件下，發生醯化反應，得到通式(III)的化合物或其可藥用的鹽， A compound of general formula (IIIA) or a salt thereof and a compound of general formula (IB) or a salt thereof, under alkaline conditions, undergo an acylation reaction to obtain a compound of general formula (III) or a pharmaceutically acceptable salt thereof,

其中， in,

X為鹵素；較佳為氯原子； X is a halogen; preferably a chlorine atom;

方案四 Option four

本揭露通式(I-1)所示的化合物，或其可藥用的鹽的製備方法，該方法包括： The present disclosure discloses a compound represented by general formula (I-1), or a preparation method of a pharmaceutically acceptable salt thereof, the method comprising:

(a)通式(I-IA)的化合物或其鹽與通式(IB)的化合物或其鹽，在鹼性條件下發生醯化反應，得到通式(I-1Aa)的化合物或其可藥用的鹽； (a) a compound of general formula (I-IA) or a salt thereof and a compound of general formula (IB) or a salt thereof undergo an acylation reaction under alkaline conditions to obtain a compound of general formula (I-1Aa) or a compound thereof medicinal salts;

(b)通式(I-1Aa)的化合物或其可藥用的鹽在酸性條件下發生脫保護反應，得到通式(I-1)的化合物或其可藥用的鹽； (b) deprotecting the compound of general formula (I-1Aa) or its pharmaceutically acceptable salt under acidic conditions to obtain the compound of general formula (I-1) or its pharmaceutically acceptable salt;

其中， in,

X為鹵素；較佳為氯原子； X is a halogen; preferably a chlorine atom;

L為亞(伸)烷基或

; Ring B is cycloalkyl or heterocyclyl; p is 0, 1, 2, 3, 4, 5 or 6;

方案五 Option five

本揭露通式(II-1)所示的化合物，或其可藥用的鹽的製備方法，該方法包括： The present disclosure discloses a compound represented by general formula (II-1), or a preparation method of a pharmaceutically acceptable salt thereof, the method comprising:

(a)通式(II-1A)的化合物或其鹽與通式(IB)的化合物或其鹽，在鹼性條件下發生醯化反應，得到通式(II-1Aa)的化合物或其可藥用的鹽； (a) the compound of general formula (II-1A) or its salt and the compound of general formula (IB) or its salt undergo acylation reaction under alkaline conditions to obtain the compound of general formula (II-1Aa) or its equivalent medicinal salts;

(b)通式(II-1Aa)的化合物或其可藥用的鹽在酸性條件下發生脫保護反應，得到通式(II-1)的化合物或其可藥用的鹽； (b) The compound of general formula (II-1Aa) or its pharmaceutically acceptable salt undergoes a deprotection reaction under acidic conditions to obtain the compound of general formula (II-1) or its pharmaceutically acceptable salt;

其中， in,

X為鹵素；較佳為氯原子； X is a halogen; preferably a chlorine atom;

L為亞(伸)烷基或

; Ring B is cycloalkyl or heterocyclyl; p is 0, 1, 2, 3, 4, 5 or 6;

方案六 Option six

本揭露通式(III-1)所示的化合物，或其可藥用的鹽的製備方法，該方法包括： The present disclosure discloses a compound represented by general formula (III-1), or a preparation method of a pharmaceutically acceptable salt thereof, the method comprising:

(a)通式(III-1A)的化合物或其鹽與通式(IB)的化合物或其鹽，在鹼性條件下發生醯化反應，得到通式(III-1Aa)的化合物或其可藥用的鹽； (a) the compound of general formula (III-1A) or its salt and the compound of general formula (IB) or its salt undergo acylation reaction under alkaline conditions to obtain the compound of general formula (III-1Aa) or its equivalent medicinal salts;

(b)通式(III-1Aa)的化合物或其可藥用的鹽在酸性條件下發生脫保護反應，得到通式(III-1)的化合物或其可藥用的鹽； (b) The compound of general formula (III-1Aa) or its pharmaceutically acceptable salt undergoes a deprotection reaction under acidic conditions to obtain the compound of general formula (III-1) or its pharmaceutically acceptable salt;

其中， in,

X為鹵素；較佳為氯原子； X is a halogen; preferably a chlorine atom;

L為亞(伸)烷基或

; Ring B is cycloalkyl or heterocyclyl; p is 0, 1, 2, 3, 4, 5 or 6;

方案七 Option seven

本揭露通式(I)所示的化合物或其可藥用的鹽的製備方法，該方法包括： The present disclosure discloses a preparation method of a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

通式(IC)的化合物或其鹽與通式(ID)的化合物或其鹽，在鹼性條件下，在催化劑存在下，發生偶聯反應，得到通式(I)的化合物或其可藥用的鹽， The compound of general formula (IC) or its salt and the compound of general formula (ID) or its salt, under alkaline conditions, in the presence of a catalyst, a coupling reaction occurs to obtain the compound of general formula (I) or its druggable the salt used,

其中， in,

Y為鹵素；較佳為溴原子； Y is a halogen; preferably a bromine atom;

方案八 Option eight

本揭露通式(II)所示的化合物或其可藥用的鹽的製備方法，該方法包括： The present disclosure discloses a preparation method of a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

通式(IIC)的化合物或其鹽與通式(ID)的化合物或其鹽，在鹼性條件下，在催化劑存在下，發生偶聯反應，得到通式(II)的化合物或其可藥用的鹽， A compound of general formula (IIC) or a salt thereof and a compound of general formula (ID) or a salt thereof are subjected to a coupling reaction under alkaline conditions in the presence of a catalyst to obtain a compound of general formula (II) or a pharmaceutically acceptable the salt used,

其中， in,

Y為鹵素；較佳為溴原子； Y is a halogen; preferably a bromine atom;

方案九 Option nine

本揭露通式(III)所示的化合物或其可藥用的鹽的製備方法，該方法包括： The present disclosure discloses a preparation method of a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

通式(IIIC)的化合物或其鹽與通式(ID)的化合物或其鹽，在鹼性條件下，在催化劑存在下，發生偶聯反應，得到通式(III)的化合物或其可藥用的鹽， A compound of general formula (IIIC) or a salt thereof and a compound of general formula (ID) or a salt thereof are subjected to a coupling reaction under alkaline conditions in the presence of a catalyst to obtain a compound of general formula (III) or a pharmaceutically acceptable the salt used,

其中， in,

Y為鹵素；較佳為溴原子； Y is a halogen; preferably a bromine atom;

方案十 Plan ten

通式(IAa)的化合物或其鹽與通式(IBb)的化合物或其鹽在縮合劑(較佳為HATU)和鹼性條件下發生醯胺化反應，得到通式(I)的化合物或其可藥用的鹽， A compound of general formula (IAa) or a salt thereof and a compound of general formula (IBb) or a salt thereof undergo an amidation reaction under a condensing agent (preferably HATU) and alkaline conditions to obtain a compound of general formula (I) or its pharmaceutically acceptable salts,

其中， in,

方案十一 Plan Eleven

通式(IIAa)的化合物或其鹽與通式(IBb)的化合物或其鹽在縮合劑(較佳為HATU)和鹼性條件下發生醯胺化反應，得到通式(II)的化合物或其可藥用的鹽， A compound of general formula (IIAa) or a salt thereof and a compound of general formula (IBb) or a salt thereof undergo an amidation reaction under a condensing agent (preferably HATU) and alkaline conditions to obtain a compound of general formula (II) or its pharmaceutically acceptable salts,

其中， in,

方案十二 Plan twelve

通式(IIIAa)的化合物或其鹽與通式(IBb)的化合物或其鹽在縮合劑(較佳為HATU)和鹼性條件下發生醯胺化反應，得到通式(III)的化合物或其可藥用的鹽， A compound of general formula (IIIAa) or a salt thereof and a compound of general formula (IBb) or a salt thereof undergo an amidation reaction under a condensing agent (preferably HATU) and alkaline conditions to obtain a compound of general formula (III) or its pharmaceutically acceptable salts,

其中， in,

以上合成方案中提供鹼性條件的試劑包括有機鹼和無機鹼類，該有機鹼類包括但不限於三乙胺、吡啶、N,N-二異丙基乙胺、正丁基鋰、二異丙基胺基鋰、醋酸鈉、醋酸鉀、第三丁醇鈉、第三丁醇鉀或1,8-二氮雜二環十一碳-7-烯，該無機鹼類包括但不限於氫化鈉、磷酸鉀、碳酸鈉、碳酸鉀、碳酸銫、氫氧化鈉、氫氧化鋰、氫氧化鋰一水合物和氫氧化鉀；其中方案一至六中提供鹼性條件的試劑較佳為吡啶；方案七至九中提供鹼性條件的試劑較佳為碳酸銫；方案十至十二中提供鹼性條件的試劑較佳為N,N-二異丙基乙胺。 The reagents providing basic conditions in the above synthesis scheme include organic bases and inorganic bases, the organic bases include but not limited to triethylamine, pyridine, N,N -diisopropylethylamine, n-butyl lithium, diiso Lithium propylamide, sodium acetate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide or 1,8-diazabicycloundec-7-ene, the inorganic bases include but are not limited to hydrogenation Sodium, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, lithium hydroxide monohydrate and potassium hydroxide; wherein the reagent providing alkaline conditions in schemes one to six is preferably pyridine; scheme The reagent providing basic conditions in Schemes 7 to 9 is preferably cesium carbonate; the reagent providing basic conditions in Schemes 10 to 12 is preferably N,N -diisopropylethylamine.

以上合成方案七至九中的催化劑包括但不限於雙(二亞芐基丙酮)鈀、雙(二亞芐基丙酮)鈀/4,5-雙二苯基膦-9,9-二甲基氧雜蒽、四-三苯基鱗鈀、二氯化鈀、醋酸鈀、甲烷磺酸(2-二環己基膦)-3,6-二甲氧基-2,4',6'-三異丙基-1,1'-聯苯)(2'-胺基-1,1'-聯苯-2-基)鈀(II)、1,1’-雙(二苄基磷)二氯二戊鐵鈀、[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀、[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀二氯甲烷絡合物、三(二亞苄基丙酮)二鈀，較佳為雙(二亞芐基丙酮)鈀或雙(二亞芐基丙酮)鈀/4,5-雙二苯基鱗-9,9-二甲基氧雜蒽。 Catalysts in the above synthesis schemes 7 to 9 include but are not limited to bis(dibenzylideneacetone)palladium, bis(dibenzylideneacetone)palladium/4,5-bisdiphenylphosphine-9,9-dimethyl Xanthene, tetrakis-triphenylphosphonium palladium, palladium dichloride, palladium acetate, methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2,4',6'-tri Isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II), 1,1'-bis(dibenzylphosphine)dichloro Dipentyl iron palladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride Dichloromethane complex, tris(dibenzylideneacetone)dipalladium, preferably bis(dibenzylideneacetone)palladium or bis(dibenzylideneacetone)palladium/4,5-bisdiphenylphosphonium -9,9-Dimethylxanthene.

以上合成方案十至十二中的醯胺化反應在縮合劑存在下進行，該縮合劑較佳為O-(7-氮雜苯并***-1-基)-N,N,N’,N’-四甲基脲六氟磷酸鹽(HATU)。 The amidation reaction in the above synthesis schemes 10 to 12 is carried out in the presence of a condensing agent, the condensing agent is preferably O- (7-azabenzotriazol-1-yl) -N,N,N', N' -tetramethyluronium hexafluorophosphate (HATU).

以上合成方案四至六中的脫保護反應較佳在酸性條件下進行，提供酸性條件的試劑較佳為三氟乙酸。 The deprotection reactions in the above synthesis schemes 4 to 6 are preferably carried out under acidic conditions, and the reagent providing acidic conditions is preferably trifluoroacetic acid.

上述步驟的反應較佳在溶劑中進行，所用的溶劑包括但不限於：吡啶、乙二醇二甲醚、醋酸、甲醇、乙醇、乙腈、正丁醇、甲苯、四氫呋喃、二氯甲烷、石油醚、乙酸乙醋、正己烷、二甲基亞碸、1,4-二噁烷、水、N,N-二甲基甲醯胺、N,N-二甲基乙醯胺、1,2-二溴乙烷及其混合物。 The reaction of the above steps is preferably carried out in a solvent, and the solvent used includes but is not limited to: pyridine, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether , ethyl acetate, n-hexane, dimethylsulfoxide, 1,4-dioxane, water, N,N -dimethylformamide, N,N -dimethylacetamide, 1,2- Dibromoethane and its mixtures.

以下結合實施例用於進一步描述本揭露，但這些實施例並非限制著本揭露的範圍。 The following examples are used to further describe the present disclosure, but these examples do not limit the scope of the present disclosure.

實施例 Example

化合物的結構是藉由核磁共振(NMR)或/和質譜(MS)來確定的。NMR位移(d)以10-6(ppm)的單位給出。NMR的測定是用Bruker AVANCE NEO 500M核磁儀，測定溶劑為氘代二甲基亞碸(DMSO-d₆)、氘代氯仿(CDCl₃)、氘代甲醇(CD₃OD)，內標為四甲基矽烷(TMS)。 Compound structures were determined by nuclear magnetic resonance (NMR) or/and mass spectroscopy (MS). NMR shifts (d) are given in units of 10-6 (ppm). The determination of NMR is carried out with a Bruker AVANCE NEO 500M nuclear magnetic instrument, and the determination solvent is deuterated dimethyl sulfide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), and the internal standard is four Methylsilane (TMS).

MS的測定用Agilent 1200/1290 DAD-6110/6120 Quadrupole MS液質聯用儀(生產商：Agilent，MS型號：6110/6120 Quadrupole MS)、waters ACQuity UPLC-QD/SQD(生產商：waters，MS型號：waters ACQuity Qda Detector/waters SQ Detector)、THERMO Ultimate 3000-Q Exactive(生產商：THERMO，MS型號：THERMO Q Exactive)。 The determination of MS uses Agilent 1200/1290 DAD-6110/6120 Quadrupole MS liquid mass spectrometer (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS), waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS Model: waters ACQuity Qda Detector/waters SQ Detector), THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

高效液相色譜法(HPLC)分析使用Agilent HPLC 1200DAD、Agilent HPLC 1200VWD和Waters HPLC e2695-2489高效液相色譜儀。 High-performance liquid chromatography (HPLC) was analyzed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high-performance liquid chromatography.

手性HPLC分析測定使用Agilent 1260 DAD高效液相色譜儀。 Chiral HPLC analysis and determination using Agilent 1260 DAD high performance liquid chromatography.

高效液相製備使用Waters 2545-2767、Waters 2767-SQ Detecor 2、Shimadzu LC-20AP和Gilson GX-281製備型色譜儀。 For HPLC preparation, Waters 2545-2767, Waters 2767-SQ Detecor 2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs were used.

手性製備使用Shimadzu LC-20AP製備型色譜儀。 Chiral preparation A Shimadzu LC-20AP preparative chromatograph was used.

CombiFlash快速製備儀使用Combiflash Rf200(TELEDYNE ISCO)。 The CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).

薄層層析矽膠板使用煙臺黃海HSGF254或青島GF254矽膠板，薄層色譜法(TLC)使用的矽膠板採用的規格是0.15mm~0.2mm，薄層層析分離純化產品採用的規格是0.4mm~0.5mm。 The thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin-layer chromatography (TLC) is 0.15mm~0.2mm, and the specification of thin-layer chromatography separation and purification products is 0.4mm. ~0.5mm.

矽膠管柱色譜法一般使用煙臺黃海矽膠200~300目矽膠為載體。 Silica gel column chromatography generally uses Yantai Huanghai silica gel 200~300 mesh silica gel as the carrier.

激酶平均抑制率及IC50值的測定用NovoStar酶標儀(德國BMG公司)。 Kinase average inhibition rate and IC50 value were determined with NovoStar microplate reader (BMG Company, Germany).

本揭露的已知的起始原料可以採用或按照本領域已知的方法來合成，或可購買自ABCR GmbH & Co.KG，Acros Organics，Aldrich Chemical Company，韶遠化學科技(Accela ChemBio Inc)、達瑞化學品等公司。 The known starting materials of the present disclosure can be used or synthesized according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc), Darui Chemicals and other companies.

實施例中無特殊說明，反應均能夠在氬氣氛或氮氣氛下進行。 Unless otherwise specified in the examples, the reactions can all be carried out under an argon atmosphere or a nitrogen atmosphere.

氬氣氛或氮氣氛是指反應瓶連接一個約1L容積的氬氣或氮氣氣球。 The argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 L.

氫氣氛是指反應瓶連接一個約1L容積的氫氣氣球。 The hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

加壓氫化反應使用Parr 3916EKX型氫化儀和清藍QL-500型氫氣發生器或HC2-SS型氫化儀。 The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenator.

氫化反應通常抽真空，充入氫氣，重複操作3次。 The hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.

微波反應使用CEM Discover-S 908860型微波反應器。 For the microwave reaction, a CEM Discover-S 908860 microwave reactor was used.

實施例中無特殊說明，溶液是指水溶液。 Unless otherwise specified in the examples, the solution refers to an aqueous solution.

實施例中無特殊說明，反應的溫度為室溫，為20℃~30℃。 Unless otherwise specified in the examples, the temperature of the reaction is room temperature, which is 20° C. to 30° C.

實施例中的反應進程的監測採用薄層色譜法(TLC)，反應所使用的展開劑，純化化合物採用的管柱層析的沖提劑的體系和薄層色譜法的展開劑體系包括：A：二氯甲烷/甲醇體系，溶劑的體積比根據化合物的極性不同而進行調節，也可以加入少量的三乙胺和醋酸等鹼性或酸性試劑進行調節。 The monitoring of the reaction process in the embodiment adopts thin-layer chromatography (TLC), the developing agent used in the reaction, the system of the eluting agent of the column chromatography adopted by the purified compound and the developing agent system of the thin-layer chromatography include: A : Dichloromethane/methanol system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and it can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.

實施例1 Example 1

N-(4-氟苯基)-N'-(5-((7-甲氧基-6-(甲基胺基甲醯基)喹啉-4-基)氧基)吡啶-2-基)環丙烷-1,1-二甲醯胺1 N -(4-fluorophenyl) -N '-(5-((7-methoxy-6-(methylaminoformyl)quinolin-4-yl)oxy)pyridin-2-yl ) cyclopropane-1,1-dimethylamide 1

第一步 first step

4-((6-胺基吡啶-3-基)氧基)-7-甲氧基-N-甲基喹啉-6-甲醯胺1b 4-((6-aminopyridin-3-yl)oxy)-7-methoxy- N -methylquinoline-6-formamide 1b

化合物4-氯-7-甲氧基-N-甲基喹啉-6-甲醯胺1a(501mg，1.99mmol，採用專利申請“WO2019148043A1中說明書第168頁的實施例中間體29”公開的方法製備而得)溶於二甲亞碸(5mL)中，加入6-胺基吡啶-3-酚(220mg,1.99mmol)和氫氧化鉀溶液(2M，0.1mL)，加熱到85 ℃反應2小時。冷卻至室溫，反應液減壓濃縮後用矽膠管柱色譜法以沖提劑體系A純化殘餘物，得到標題產物1b(400mg，產率：62%)。 Compound 4-chloro-7-methoxy- N -methylquinoline-6-formamide 1a (501mg, 1.99mmol, using the method disclosed in the patent application "Example Intermediate 29 on page 168 of the specification in WO2019148043A1" Prepared) was dissolved in dimethylsulfoxide (5mL), added 6-aminopyridin-3-ol (220mg, 1.99mmol) and potassium hydroxide solution (2M, 0.1mL), heated to 85 ℃ for 2 hours . After cooling to room temperature, the reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with eluent system A to obtain the title product 1b (400 mg, yield: 62%).

MS m/z(ESI)：325.1[M+1] MS m/z(ESI): 325.1[M+1]

第二步 second step

將化合物1b(170mg，524.15μmol)，化合物1-((4-氟苯基)胺甲醯基)環丙烷-1-甲醯氯1c(130mg，537.98μmol，採用專利申請“EP3750893A1中說明書第14頁的實施例公用中間體”公開的方法製備而得)溶於吡啶(10mL)，攪拌12小時。反應液減壓濃縮後，用高效液相色譜法(Gilson281，色譜管柱：SharpSil-T C18 150*30mm,5μm；流動相1：水(含10mmol/L的碳酸氫銨)；流動相2：乙腈；15分鐘梯度：乙腈38%-90%，流速：30mL/min)純化殘餘物，得標題產物1(98mg，產率：35.0%)。 Compound 1b (170 mg, 524.15 μmol), compound 1-((4-fluorophenyl)aminoformyl)cyclopropane-1-formyl chloride 1c (130mg, 537.98 μmol) were prepared by using the patent application "EP3750893A1 in the specification No. 14 (prepared by the method disclosed in the examples on page Common Intermediates)) was dissolved in pyridine (10 mL), and stirred for 12 hours. After the reaction solution was concentrated under reduced pressure, use high performance liquid chromatography (Gilson281, chromatographic column: SharpSil-T C18 150*30mm, 5 μm; mobile phase 1: water (containing 10mmol/L ammonium bicarbonate); mobile phase 2: Acetonitrile; 15 minutes gradient: acetonitrile 38%-90%, flow rate: 30mL/min) to obtain the title product 1 (98mg, yield: 35.0%).

MS m/z(ESI)：530.2[M+1] MS m/z(ESI):530.2[M+1]

¹H NMR(500MHz,DMSO-d ₆)δ 11.18(s,1H),9.76(s,1H),8.68(d,J=5.3Hz,1H),8.63(s,1H),8.40-8.35(m,2H),8.23(d,J=9.0Hz,1H),7.85(dd,J=9.0,2.9Hz,1H),7.65-7.59(m,2H),7.54(s,1H),7.23-7.14(m,2H),6.56(d,J=5.3Hz,1H),4.03(s,3H),2.85(d,J=4.6Hz,3H),1.65-1.53(m,4H)。 ¹ H NMR (500MHz,DMSO- d ₆ )δ 11.18(s,1H),9.76(s,1H),8.68(d, J =5.3Hz,1H),8.63(s,1H),8.40-8.35(m ,2H),8.23(d, J =9.0Hz,1H),7.85(dd, J =9.0,2.9Hz,1H),7.65-7.59(m,2H),7.54(s,1H),7.23-7.14( m,2H),6.56(d, J =5.3Hz,1H),4.03(s,3H),2.85(d, J =4.6Hz,3H),1.65-1.53(m,4H).

實施例2 Example 2

N-(4-氟苯基)-N'-[5-[[7-甲氧基-6-(甲基胺基甲醯基)-喹啉-4-基]氧基]吡嗪-2-基]環丙烷-1,1-二甲醯胺2 N -(4-fluorophenyl) -N' -[5-[[7-methoxy-6-(methylaminoformyl)-quinolin-4-yl]oxy]pyrazine-2 -yl]cyclopropane-1,1-dimethylamide 2

第一步 first step

N-(4-氟苯基)環丙烷-1,1-二甲醯胺2a N- (4-fluorophenyl)cyclopropane-1,1-dimethylamide 2a

將1c(2g，8.27mmol)溶於四氫呋喃(20mL)，冰浴下，將25-28%的胺水(30mL)滴入反應瓶中，升至室溫，攪拌1小時。用二氯甲烷萃取(100mL×2)，合併有機相，無水硫酸鈉乾燥，過濾，濾液減壓濃縮後用矽膠管柱色譜法以沖提劑體系A純化得到標題產物2a(1.8g，產率：97.8%)。 1c (2g, 8.27mmol) was dissolved in tetrahydrofuran (20mL), and 25-28% amine water (30mL) was dropped into the reaction flask under ice-cooling, raised to room temperature, and stirred for 1 hour. Extract with dichloromethane (100mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, the filtrate is concentrated under reduced pressure and purified by silica gel column chromatography with eluent system A to obtain the title product 2a (1.8g, yield : 97.8%).

MS m/z(ESI)：223.1[M+1]。 MS m/z (ESI): 223.1 [M+1].

第二步 second step

4-羥基-7-甲氧基-N-甲基喹啉-6-甲醯胺2c 4-Hydroxy-7-methoxy- N -methylquinoline-6-carboxamide 2c

將化合物7-甲氧基-4-側氧-1,4-二氫喹啉-6-羧酸甲酯2b(10g，42.87mmol，上海韶遠試劑有限公司)溶於30%甲胺的乙醇溶液中(200mL，上海泰坦科技股份有限公司)，室溫攪拌16小時，反應液減壓濃縮後得粗品標題產物2c(9.7g，產率：97.4%)，產物不經純化直接用於下一步。 Compound 7-methoxy-4-oxo-1,4-dihydroquinoline-6-carboxylic acid methyl ester 2b (10g, 42.87mmol, Shanghai Shaoyuan Reagent Co., Ltd.) was dissolved in 30% methylamine in ethanol Solution (200mL, Shanghai Titan Science and Technology Co., Ltd.), stirred at room temperature for 16 hours, the reaction solution was concentrated under reduced pressure to obtain the crude title product 2c (9.7g, yield: 97.4%), and the product was directly used in the next step without purification .

MS m/z(ESI)：233.1[M+1]。 MS m/z (ESI): 233.1 [M+1].

第三步 third step

4-((5-溴吡嗪-2-基)氧基)-7-甲氧基-N-甲基喹啉-6-甲醯胺2d 4-((5-bromopyrazin-2-yl)oxy)-7-methoxy- N -methylquinoline-6-formamide 2d

將化合物2c(2.5g，10.76mmol)溶於N,N-二甲基甲醯胺(100mL)中，加入碳酸銫(8.7g，26.9mmol，上海韶遠試劑有限公司)，攪拌，80℃反應1小時，將2,5-二溴吡嗪(2.5g，10.76mmol，上海韶遠試劑有限公司)溶於N,N-二甲基甲醯胺(2mL)，在80℃條件下滴加入反應瓶中，繼續反應1小時。將反應液冷卻至室溫，緩慢倒入800mL水中，加入乙酸乙酯萃取(300mL×3)，合併有機相，無水硫酸鈉乾燥，過濾，濾液減壓濃縮後用矽膠管柱色譜法以沖提劑體系A純化得到標題產物2d(840mg，產率：20%)。 Dissolve compound 2c (2.5g, 10.76mmol) in N,N -dimethylformamide (100mL), add cesium carbonate (8.7g, 26.9mmol, Shanghai Shaoyuan Reagent Co., Ltd.), stir, and react at 80°C For 1 hour, 2,5-dibromopyrazine (2.5g, 10.76mmol, Shanghai Shaoyuan Reagent Co., Ltd.) was dissolved in N , N -dimethylformamide (2mL), and added dropwise to the reaction at 80°C In the bottle, the reaction was continued for 1 hour. Cool the reaction solution to room temperature, slowly pour it into 800mL of water, add ethyl acetate for extraction (300mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and use silica gel column chromatography to elute Purification of reagent system A afforded the title product 2d (840 mg, yield: 20%).

MS m/z(ESI)：391.0[M+1]。 MS m/z (ESI): 391.0 [M+1].

第四步 the fourth step

將化合物2d(810mg，2.08mmol)溶於甲苯(150mL)中，加入化合物2a(925mg，4.16mmol)，碳酸銫(2.0g，6.24mmol，上海韶遠試劑有限公司)，4,5-雙二苯基鱗-9,9-二甲基氧雜蒽(721mg，1.24mmol，上海韶遠試劑有限公司)，通入氮氣兩次，排出空氣，加入雙(二亞芐基丙酮)鈀(571mg，0.62mmol，北京百靈威科技有限公司)，通入氮氣三次，排出空氣，加入預先熱好的90℃油浴鍋中，攪拌16小時。冷至室溫，反應液減壓濃縮後用高效液相色譜法(Gilson281，色譜管柱：SharpSil-T C18 150*30mm，5μm；流動相1：水(含10mmol/L的碳酸氫銨)；流動相2：乙腈；20分鐘梯度：25%-45%，流速：30mL/min)純化得標題產物2(410mg，產率：37.1%)。 Compound 2d (810mg, 2.08mmol) was dissolved in toluene (150mL), and compound 2a (925mg, 4.16mmol), cesium carbonate (2.0g, 6.24mmol, Shanghai Shaoyuan Reagent Co., Ltd.), 4,5-bisbis Phenylphosphonium-9,9-dimethylxanthene (721mg, 1.24mmol, Shanghai Shaoyuan Reagent Co., Ltd.), nitrogen was passed through twice, and the air was exhausted, and bis(dibenzylideneacetone)palladium (571mg, 0.62mmol, Beijing Bailingwei Technology Co., Ltd.), nitrogen gas was introduced three times, the air was exhausted, and the mixture was added to a pre-heated 90°C oil bath, and stirred for 16 hours. After being cooled to room temperature, the reaction solution was concentrated under reduced pressure and then subjected to high performance liquid chromatography (Gilson281, chromatographic column: SharpSil-T C18 150*30mm, 5 μm; mobile phase 1: water (containing 10mmol/L ammonium bicarbonate); Mobile phase 2: acetonitrile; 20 minutes gradient: 25%-45%, flow rate: 30mL/min) was purified to obtain the title product 2 (410mg, yield: 37.1%).

MS m/z(ESI)：531.2[M+1]。 MS m/z (ESI): 531.2 [M+1].

¹H NMR(500MHz,DMSO-d ₆)δ 11.39(d,1H),9.80(s,1H),9.01(s,1H),8.80(d,1H),8.60(s,1H),8.48(s,1H),8.40-8.35(m,1H),7.60-7.65(m,2H),7.57(s,1H),7.18(t,2H),7.04(d,1H),4.04(s,3H),2.83(d,3H),1.60-1.64(m,4H)。 ¹ H NMR (500MHz,DMSO- d ₆ )δ 11.39(d,1H),9.80(s,1H),9.01(s,1H),8.80(d,1H),8.60(s,1H),8.48(s ,1H),8.40-8.35(m,1H),7.60-7.65(m,2H),7.57(s,1H),7.18(t,2H),7.04(d,1H),4.04(s,3H), 2.83(d,3H),1.60-1.64(m,4H).

實施例3 Example 3

N-環己基-N-(5-((7-甲氧基-6-(甲基胺基甲醯基)喹啉-4-基)氧基)吡啶-2-基)環丙烷-1,1-二甲醯胺3 N -cyclohexyl- N- (5-((7-methoxy-6-(methylaminoformyl)quinolin-4-yl)oxy)pyridin-2-yl)cyclopropane-1, 1-Diformamide 3

第一步 first step

1-((5-((7-甲氧基-6-(甲基胺基甲醯基)喹啉-4-基)氧基)吡啶-2-基)胺甲醯基)環丙烷-1-羧酸甲酯3b 1-((5-((7-methoxy-6-(methylaminoformyl)quinolin-4-yl)oxy)pyridin-2-yl)aminoformyl)cyclopropane-1 - Methyl carboxylate 3b

將化合物1b(200mg,0.62mmol)，1,1-環丙基二甲酸單甲酯3a(106mg,0.74mmol)溶於N,N-二甲基甲醯胺(5mL)，加入O-(7-氮雜苯并***-1-基)-N,N,N’,N’-四甲基脲六氟磷酸鹽(282mg，0.74mmol，上海韶遠試劑有限公司)，N,N-二異丙基乙胺(240mg，1.86mmol，阿達瑪斯試劑有限公司)，室溫攪拌4小時。減壓濃縮除去溶劑，所得殘餘物用矽膠管柱色譜法以沖提劑體系A純化得到標題產物3b(180mg，產率：64.8%)。 Compound 1b (200mg, 0.62mmol), 1,1-cyclopropyl dicarboxylic acid monomethyl ester 3a (106mg, 0.74mmol) was dissolved in N,N -dimethylformamide (5mL), and O- (7 -Azabenzotriazol-1-yl) -N,N,N',N' -tetramethyluronium hexafluorophosphate (282mg, 0.74mmol, Shanghai Shaoyuan Reagent Co., Ltd.), N,N -di Isopropylethylamine (240 mg, 1.86 mmol, Adamas Reagent Co., Ltd.), stirred at room temperature for 4 hours. The solvent was removed by concentration under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to obtain the title product 3b (180 mg, yield: 64.8%).

MS m/z(ESI)：451.1[M+1]。 MS m/z (ESI): 451.1 [M+1].

第二步 second step

1-((5-((7-甲氧基-6-(甲基胺基甲醯基)喹啉-4-基)氧基)吡啶-2-基)胺甲醯基)環丙烷-1-羧酸3c 1-((5-((7-methoxy-6-(methylaminoformyl)quinolin-4-yl)oxy)pyridin-2-yl)aminoformyl)cyclopropane-1 -Carboxylic acid 3c

化合物3b(80mg，0.18mmol)溶於6.6mL甲醇、四氫呋喃和水(V/V/V=5：5：1)的混合溶劑中，加入氫氧化鋰一水合物(37mg，0.88mmol)，室溫攪拌2小時。減壓濃縮除去大部分溶劑，加入1M鹽酸至反應液pH為3~4，有固體析出，過濾，收集濾餅，真空乾燥，得到標題產物3c(77mg，產率：99%)。 Compound 3b (80 mg, 0.18 mmol) was dissolved in 6.6 mL of a mixed solvent of methanol, tetrahydrofuran and water (V/V/V=5:5:1), lithium hydroxide monohydrate (37 mg, 0.88 mmol) was added, and the Stir warm for 2 hours. Concentrate under reduced pressure to remove most of the solvent, add 1M hydrochloric acid until the pH of the reaction solution is 3~4, a solid precipitates, filter, collect the filter cake, and dry in vacuo to obtain the title product 3c (77 mg, yield: 99%).

MS m/z(ESI)：437.1[M+1]。 MS m/z (ESI): 437.1 [M+1].

第三步 third step

化合物3c(77mg,0.18mmol)，環己胺(21mg，0.21mmol，阿達瑪斯試劑有限公司)溶於N,N-二甲基甲醯胺(3mL)，加入O-(7-氮雜苯并***-1-基)-N,N,N’,N’-四甲基脲六氟磷酸鹽(81mg，0.21mmol，上海韶遠試劑有限公司)，N,N-二異丙基乙胺(182mg,1.41mmol)，室溫攪拌2小時。過濾，減壓濃縮除去溶劑，所得殘餘物用高效液相色譜法(Waters-2545，色譜管柱：SharpSil-T，30*150mm,5μm；流動相1：水(含10mmol/L的碳酸氫銨)；流動相2：乙腈；12分鐘梯度：乙腈：35%-50%，流速：30mL/min)純化，得到標題產物3(11mg，產率：12.0%)。 Compound 3c (77mg, 0.18mmol), cyclohexylamine (21mg, 0.21mmol, Adamas Reagent Co., Ltd.) was dissolved in N,N -dimethylformamide (3mL), and O- (7-azabenzene Triazol-1-yl) -N,N,N',N' -tetramethyluronium hexafluorophosphate (81mg, 0.21mmol, Shanghai Shaoyuan Reagent Co., Ltd.), N,N -diisopropylethyl Amine (182mg, 1.41mmol), stirred at room temperature for 2 hours. Filtration, concentrated under reduced pressure to remove solvent, the residue obtained by high performance liquid chromatography (Waters-2545, chromatographic column: SharpSil-T, 30*150mm, 5 μm; mobile phase 1: water (containing 10mmol/L of ammonium bicarbonate ); mobile phase 2: acetonitrile; 12 minutes gradient: acetonitrile: 35%-50%, flow rate: 30mL/min) purification to obtain the title product 3 (11 mg, yield: 12.0%).

MS m/z(ESI)：518.2[M+1]。 MS m/z (ESI): 518.2 [M+1].

¹H NMR(500MHz,DMSO-d ₆)：10.82(s,1H),8.67(d,1H)，8.61(s,1H)，8.30-8.44(m,2H)，8.18(d,1H),7.82(dd,1H),7.60(d,1H),7.52(s,1H),6.55(d,1H),4.02(s,3H)，3.58-3.69(m,1H),2.84(d,3H),1.62-1.79(m,4H),1.55-1.61(m,1H),1.39-1.54(d,4H),1.21-1.26(m,5H)。 ¹ H NMR (500MHz, DMSO- d ₆ ): 10.82(s,1H), 8.67(d,1H), 8.61(s,1H), 8.30-8.44(m,2H), 8.18(d,1H), 7.82 (dd,1H),7.60(d,1H),7.52(s,1H),6.55(d,1H),4.02(s,3H),3.58-3.69(m,1H),2.84(d,3H), 1.62-1.79 (m, 4H), 1.55-1.61 (m, 1H), 1.39-1.54 (d, 4H), 1.21-1.26 (m, 5H).

實施例4 Example 4

N-(5-((7-((1-胺基環丙基)甲氧基)-6-(甲基胺基甲醯基)喹啉-4-基)氧基)吡啶-2-基)-N-(4-氟苯基)環丙烷-1,1-二甲醯胺4 N -(5-((7-((1-aminocyclopropyl)methoxy)-6-(methylaminoformyl)quinolin-4-yl)oxy)pyridin-2-yl )-N-(4-fluorophenyl)cyclopropane-1,1- dimethylamide 4

第一步 first step

(1-((第三丁氧基羰基)胺基)環丙基)甲基甲磺酸酯4b (1-((tertiary butoxycarbonyl)amino)cyclopropyl)methyl mesylate 4b

化合物(1-(羥甲基)環丙基)胺基甲酸第三丁酯4a(1.8g，9.6mmol)溶於二氯甲烷(15mL)，加入三乙胺(2.91g，28.75mmol)。0℃下滴加甲磺醯氯(1.31g，11.49mmol)，室溫反應0.5小時。用乙酸乙酯萃取(30mL×3)，合併有機相，用無水硫酸鈉乾燥，濃縮得到標題產物4b粗品(2.5g，產率：98%)。 Compound (tert-butyl 1-(hydroxymethyl)cyclopropyl)carbamate 4a (1.8 g, 9.6 mmol) was dissolved in dichloromethane (15 mL), and triethylamine (2.91 g, 28.75 mmol) was added. Methanesulfonyl chloride (1.31 g, 11.49 mmol) was added dropwise at 0°C, and reacted at room temperature for 0.5 hours. Extracted with ethyl acetate (30 mL×3), combined the organic phases, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product of the title product 4b (2.5 g, yield: 98%).

第二步 second step

4-氯-7-羥基-N-甲基喹啉-6-甲醯胺4c 4-Chloro-7-hydroxy- N -methylquinoline-6-carboxamide 4c

化合物1a(1g，3.98mmol)溶於二氯甲烷(50mL)，0℃下滴加三溴化硼二氯甲烷溶液(1M，39.89mL)。升至室溫反應5小時。加入10mL甲醇淬滅反應，用飽和碳酸氫鈉溶液將溶液pH調節至弱酸性。減壓濃縮後殘餘物用矽膠管柱色譜法以沖提劑體系A純化得到標題產物4c(944mg，產率：99%)。 Compound 1a (1 g, 3.98 mmol) was dissolved in dichloromethane (50 mL), and boron tribromide dichloromethane solution (1M, 39.89 mL) was added dropwise at 0°C. Rise to room temperature and react for 5 hours. The reaction was quenched by adding 10 mL of methanol, and the pH of the solution was adjusted to weak acidity with saturated sodium bicarbonate solution. After concentration under reduced pressure, the residue was purified by silica gel column chromatography with eluent system A to obtain the title product 4c (944 mg, yield: 99%).

MS m/z(ESI)：237.1[M+1]。 MS m/z (ESI): 237.1 [M+1].

第三步 third step

(1-(((4-氯-6-(甲基胺基甲醯基)喹啉-7-基)氧基)甲基)環丙基)胺基甲酸第三丁酯4d Tertiary butyl (1-(((4-chloro-6-(methylaminoformyl)quinolin-7-yl)oxy)methyl)cyclopropyl)carbamate 4d

將化合物4c(900mg，3.80mmol)和化合物4b(2.0g，7.53mmol)溶於N,N-二甲基甲醯胺(10mL)，加入無水碳酸鉀(2.6g，18.81mmol)和碘化鉀(1.8g，10.84mmol)。85℃攪拌16小時。冷卻至室溫，反應液減壓濃縮後用矽膠管柱色譜法以沖提劑體系A純化得到標題產物4d(600mg，產率：38.8%)。 Compound 4c (900mg, 3.80mmol) and compound 4b (2.0g, 7.53mmol) were dissolved in N,N -dimethylformamide (10mL), anhydrous potassium carbonate (2.6g, 18.81mmol) and potassium iodide (1.8 g, 10.84 mmol). Stir at 85°C for 16 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system A to obtain the title product 4d (600 mg, yield: 38.8%).

MS m/z(ESI)：406.2[M+1]。 MS m/z (ESI): 406.2 [M+1].

第四步 the fourth step

(1-(((4-((6-胺基吡啶-3-基)氧基)-6-(甲基胺基甲醯基)喹啉-7-基)氧基)甲基)環丙基胺基甲酸第三丁酯4e (1-(((4-((6-aminopyridin-3-yl)oxy)-6-(methylaminoformyl)quinolin-7-yl)oxy)methyl)cyclopropyl Tertiary butyl carbamate 4e

化合物4d(600mg，1.47mmol)溶於二甲基亞碸(10mL)，加入6-胺基吡啶-3-酚(162mg，1.47mmol)，加入氫氧化鉀溶液(1M，3mL)，加熱到85℃反應2小時。冷卻至室溫，反應也減壓濃縮後用矽膠管柱色譜法以沖提劑體系A純化得到標題產物4e(300mg，產率：42%)。 Compound 4d (600mg, 1.47mmol) was dissolved in dimethylsulfoxide (10mL), added 6-aminopyridin-3-ol (162mg, 1.47mmol), added potassium hydroxide solution (1M, 3mL), heated to 85 °C for 2 hours. After cooling to room temperature, the reaction was also concentrated under reduced pressure and purified by silica gel column chromatography with eluent system A to obtain the title product 4e (300 mg, yield: 42%).

MS m/z(ESI)：480.1[M+1]。 MS m/z (ESI): 480.1 [M+1].

第五步 the fifth step

(1-(((4-((6-(1-((4-氟苯基)胺基甲醯基)環丙烷-1-甲醯胺基)吡啶-3-基)氧基)-6-(甲基胺基甲醯基)喹啉-7-基)氧基)甲基)環丙基)胺基甲酸第三丁酯4f (1-(((4-((6-(1-((4-fluorophenyl)aminoformyl)cyclopropane-1-formamido)pyridin-3-yl)oxy)-6 -(Methylaminoformyl)quinolin-7-yl)oxy)methyl)cyclopropyl)carbamate tertiary butyl ester 4f

化合物4e(130mg，271.10μmol)和化合物1c(130mg，537.97μmol)溶於吡啶(10mL)，室溫攪拌16小時。反應液減壓濃縮後用矽膠管柱色譜法以沖提劑體系A純化得到標題產物4f(130mg，產率：70%)。 Compound 4e (130 mg, 271.10 μmol) and compound 1c (130 mg, 537.97 μmol) were dissolved in pyridine (10 mL), and stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system A to obtain the title product 4f (130 mg, yield: 70%).

MS m/z(ESI)：685.3[M+1]。 MS m/z (ESI): 685.3 [M+1].

第六步 step six

化合物4f(130mg，189.86μmol)溶於二氯甲烷(5mL)，0℃下滴加三氟乙酸(1mL)，室溫反應1小時。室溫濃縮反應液，用飽和碳酸氫鈉溶液調節反應液pH為8，濃縮，殘餘物用高效液相色譜法(Waters-2545，色譜管柱：YMC Triar-Exrs Prep C18 150*30mm,5μm；流動相1：水(含10mmol/L的碳酸氫銨)；流動相2：乙腈；15分鐘梯度：乙腈：35%-47%，流速：30mL/min)純化得標題產物4(86mg，產率77%)。 Compound 4f (130 mg, 189.86 μmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added dropwise at 0° C., and reacted at room temperature for 1 hour. Concentrate the reaction solution at room temperature, adjust the pH of the reaction solution to 8 with saturated sodium bicarbonate solution, concentrate, and use high performance liquid chromatography (Waters-2545, chromatographic column: YMC Triar-Exrs Prep C18 150*30mm, 5 μm; Mobile phase 1: water (ammonium bicarbonate containing 10mmol/L); Mobile phase 2: acetonitrile; 15 minutes gradient: acetonitrile: 35%-47%, flow rate: 30mL/min) purify title product 4 (86mg, productive rate 77%).

MS m/z(ESI)：585.2[M+1]。 MS m/z (ESI): 585.2 [M+1].

¹H NMR(500MHz,DMSO-d ₆)δ 1.18(s,1H),9.76(s,1H),8.77-8.58(m,3H),8.38(d,1H),8.22(d,1H),7.85(dd,1H),7.67-7.59(m,2H), 7.51(s,1H),7.17(t,2H),6.55(d,1H),4.17(s,2H),2.87(d,3H),2.15(s,2H),1.58(dt,4H),0.67(dt,2H),0.65-0.59(m,2H)。 ¹ H NMR (500MHz,DMSO- d ₆ )δ 1.18(s,1H),9.76(s,1H),8.77-8.58(m,3H),8.38(d,1H),8.22(d,1H),7.85 (dd,1H),7.67-7.59(m,2H), 7.51(s,1H),7.17(t,2H),6.55(d,1H),4.17(s,2H),2.87(d,3H), 2.15 (s, 2H), 1.58 (dt, 4H), 0.67 (dt, 2H), 0.65-0.59 (m, 2H).

對照例A Comparative example A

N-(4-氟苯基)-N-(2-((7-甲氧基-6-(甲基胺基甲醯基)喹啉-4-基)氧基)嘧啶-5-基) N -(4-fluorophenyl ) -N-(2-((7-methoxy-6-(methylaminoformyl)quinolin-4-yl)oxy)pyrimidin-5-yl)

環丙烷-1,1-二甲醯胺A Cyclopropane-1,1-dimethylamide A

第一步 first step

7-甲氧基-N-甲基-4-((5-硝基嘧啶-2-基)氧基)喹啉-6-甲醯胺A2 7-methoxy- N -methyl-4-((5-nitropyrimidin-2-yl)oxy)quinoline-6-formamide A2

將化合物2c(1g，4.31mmol)分散於N,N-二甲基甲醯胺(10mL)中，加入2-氯-5硝基嘧啶A1(690mg，4.33mmol，上海畢得醫藥科技股份有限公司)，三乙胺(0.48g，4.74mmol)，室溫反應5分鐘，減壓濃縮除去溶劑，所得殘餘物用矽膠管柱色譜法以沖提劑體系A純化得到標題產物A2(200mg，產率：13.1%)。 Disperse compound 2c (1g, 4.31mmol) in N,N -dimethylformamide (10mL), add 2-chloro-5-nitropyrimidine A1 (690mg, 4.33mmol, Shanghai Pide Pharmaceutical Technology Co., Ltd. ), triethylamine (0.48g, 4.74mmol), reacted at room temperature for 5 minutes, concentrated under reduced pressure to remove the solvent, and the resulting residue was purified with silica gel column chromatography to obtain the title product A2 (200mg, yield : 13.1%).

MS m/z(ESI)：356.1[M+1]。 MS m/z (ESI): 356.1 [M+1].

第二步 second step

4-((5-胺基嘧啶-2-基)氧基)-7-甲氧基-N-甲基-喹啉-6-甲醯胺A3 4-((5-aminopyrimidin-2-yl)oxy)-7-methoxy- N -methyl-quinoline-6-formamide A3

將化合物A2(180mg，0.51mmol)溶於25mL乙醇和水(V/V=4：1)的混合溶劑中，加入170mg鐵粉，再加入170mg氯化銨。加熱至90℃反應2小時，減壓濃縮除去溶劑，所得殘餘物用矽膠管柱色譜法以沖提劑體系A純化，得到標題產物A3(160mg，產率：97.1%)。 Compound A2 (180 mg, 0.51 mmol) was dissolved in 25 mL of a mixed solvent of ethanol and water (V/V=4:1), 170 mg of iron powder was added, and 170 mg of ammonium chloride was added. Heated to 90°C for 2 hours, concentrated under reduced pressure to remove the solvent, and purified the resulting residue by silica gel column chromatography with eluent system A to obtain the title product A3 (160 mg, yield: 97.1%).

MS m/z(ESI)：326.2[M+1]。 MS m/z (ESI): 326.2 [M+1].

第三步 third step

環丙烷-1,1-二甲醯胺A Cyclopropane-1,1-dimethylamide A

將化合物A3(100mg，0.31mmol)和化合物1c(90mg，0.37mmol)溶於吡啶(10mL)中，室溫攪拌反應16小時。反應液減壓濃縮後用高效液相色譜法(色譜管柱：SharpSil-T C18 150*30mm，5μm；流動相1：水(含10mmol/L的碳酸氫銨)；流動相2：乙腈；22分鐘，乙腈：36%-46%，流速：30mL/min)純化得到標題產物A(60mg，產率：36.8%)。 Compound A3 (100 mg, 0.31 mmol) and compound 1c (90 mg, 0.37 mmol) were dissolved in pyridine (10 mL), and stirred at room temperature for 16 hours. After the reaction solution was concentrated under reduced pressure, use high-performance liquid chromatography (chromatographic column: SharpSil-T C18 150*30mm, 5 μm; mobile phase 1: water (containing 10mmol/L ammonium bicarbonate); mobile phase 2: acetonitrile; 22 minutes, acetonitrile: 36%-46%, flow rate: 30mL/min) to obtain the title product A (60mg, yield: 36.8%).

MS m/z(ESI)：531.9[M+1]。 MS m/z (ESI): 531.9 [M+1].

¹H NMR(500MHz,DMSO-d ₆)δ 10.44(s,1H),10.10(s,1H),8.91(s,2H),8.87-8.89(d,1H),8.34-8.37(dd,1H),8.28(s,1H)7.62-7.65(dd,2H),7.59(s,1H),7.26-7.27(d,1H),7.13-7.16(t,2H),4.03(s,3H),2.80-2.81(d,3H),1.47(s,4H)。 ¹ H NMR (500MHz,DMSO- d ₆ )δ 10.44(s,1H),10.10(s,1H),8.91(s,2H),8.87-8.89(d,1H),8.34-8.37(dd,1H) ,8.28(s,1H)7.62-7.65(dd,2H),7.59(s,1H),7.26-7.27(d,1H),7.13-7.16(t,2H),4.03(s,3H),2.80- 2.81(d,3H), 1.47(s,4H).

生物學評價biological evaluation

測試例1、本揭露化合物對Axl、Mer、KDR和MET激酶活性具有抑制作用Test Example 1. The disclosed compound has inhibitory effect on Axl, Mer, KDR and MET kinase activities

本實驗的目的是為了測試化合物對Axl、Mer、KDR和MET的激酶活性抑制作用，根據IC₅₀大小評價化合物的體外活性。 The purpose of this experiment is to test the inhibitory effect of the compound on the kinase activity of Axl, Mer, KDR and MET, and evaluate the in vitro activity of the compound according to the IC ₅₀ size.

本揭露化合物對Axl、Mer、KDR和MET激酶活性抑制效果藉由以下的方法進行測試。 The inhibitory effects of the disclosed compounds on Axl, Mer, KDR and MET kinase activities were tested by the following methods.

一、實驗材料及儀器 1. Experimental materials and instruments

實驗儀器 laboratory apparatus

實驗材料 Experimental Materials

二、實驗步驟 2. Experimental steps

1.利用DMSO溶解化合物至10mM，5倍依次梯度稀釋9個濃度。用PBS再次稀釋之前DMSO稀釋的各梯度化合物，將化合物稀釋為首濃度50μM，5倍梯度稀釋9個濃度點。再取2μL化合物加入384孔板中(PE，6005620)。 1. Dissolve the compound to 10mM in DMSO, and serially dilute 9 concentrations by 5 times. Each gradient compound previously diluted in DMSO was diluted again with PBS, and the compound was diluted to an initial concentration of 50 μM, and 5-fold gradient dilution was performed at 9 concentration points. Another 2 μL of the compound was added to a 384-well plate (PE, 6005620).

2.根據HTRF KinEASE-TK試劑盒(Cisbio，62TK0PEC)說明書，配置酶活反應緩衝液。 2. According to the instructions of the HTRF KinEASE-TK kit (Cisbio, 62TKOPEC), configure the enzyme activity reaction buffer.

3.利用酶活緩衝液將Axl(Carna Biosciences，08-107)，Mer(Carna Biosciences，08-108)，KDR(Carna Biosciences，08-191)和MET(Carna Biosciences，08-151)蛋白依次稀釋到0.025ng/μL，0.125ng/μL，0.01ng/μL和0.05ng/μL，分別取4μL加入384孔中。室溫孵育15分鐘。 3. Use enzyme activity buffer to dilute Axl (Carna Biosciences, 08-107), Mer (Carna Biosciences, 08-108), KDR (Carna Biosciences, 08-191) and MET (Carna Biosciences, 08-151) proteins in sequence To 0.025ng/μL, 0.125ng/μL, 0.01ng/μL and 0.05ng/μL, respectively take 4μL into 384 wells. Incubate at room temperature for 15 minutes.

4.根據HTRF KinEASE-TK試劑盒說明書，利用酶活緩衝液配置ATP和受質的反應受質混合液。其中ATP濃度為100μM，受質濃度為1μM。取4μL反應受質混合液加入384孔板中，37℃反應0.5小時。 4. According to the instructions of the HTRF KinEASE-TK kit, use the enzyme activity buffer to prepare the reaction substrate mixture of ATP and substrate. The ATP concentration is 100 μM, and the substrate concentration is 1 μM. 4 μL of the reaction substrate mixture was added to a 384-well plate, and reacted at 37°C for 0.5 hours.

5.根據HTRF KinEASE-TK試劑盒說明書，配置檢測混合液。取10μL檢測混合液加入384孔板中，室溫孵育1小時。 5. According to the instructions of the HTRF KinEASE-TK kit, configure the detection mixture. Take 10 μL of the detection mixture and add it to a 384-well plate, and incubate at room temperature for 1 hour.

6.利用Envision酶標儀中的HTRF模塊讀取在665nm和620nm激發的熒光信號值，並計算比值Ratio=(665nm/620nm)×10⁴。 6. Use the HTRF module in the Envision microplate reader to read the fluorescence signal values excited at 665nm and 620nm, and calculate the ratio Ratio=(665nm/620nm)×10 ⁴ .

7.使用graphpad prism5.0軟件的log(抑制劑)vs.響應-變量斜率，根據化合物濃度的對數值和相應的比值計算得到抑制率，繪製量效曲線並計算IC₅₀值。 7. Use the log(inhibitor) vs. response-variable slope of the graphpad prism5.0 software to calculate the inhibition rate based on the logarithmic value of the compound concentration and the corresponding ratio, draw the dose-effect curve and calculate the IC ₅₀ value.

本揭露中化合物對Axl、Mer、KDR和MET激酶活性抑制藉由以上的試驗進行測定，測得的IC₅₀值見表1。 The inhibition of the kinase activity of Axl, Mer, KDR and MET by the compounds disclosed in this disclosure was determined by the above tests, and the measured IC ₅₀ values are shown in Table 1.

表1 本揭露中化合物對Axl、Mer、KDR和MET激酶活性抑制作用IC₅₀值

Table 1 The IC ₅₀ values of the inhibitory effects of the compounds in this disclosure on Axl, Mer, KDR and MET kinase activities

結論：本揭露化合物對KDR、MET、Axl、Mer的結合作用均具有明顯的抑制作用，且比對照例A相比具有更好的抑制作用。 Conclusion: The compounds disclosed in this disclosure have obvious inhibitory effects on the binding of KDR, MET, Axl, and Mer, and have better inhibitory effects than Control Example A.

測試例2：本揭露化合物在人肝微粒體中反應性代謝產物鑑定Test Example 2: Identification of Reactive Metabolites of Compounds Disclosed in Human Liver Microsomes

本揭露化合物在人肝微粒體中反應性代謝產物鑑定採用如下實驗方法： The identification of reactive metabolites of the disclosed compounds in human liver microsomes adopts the following experimental methods:

一、實驗材料及儀器 1. Experimental materials and instruments

1、磷酸緩衝液(購買自上海生工) 1. Phosphate buffer (purchased from Shanghai Sangong)

2、NADPH(ACROS，A2646-71-1) 2. NADPH (ACROS, A2646-71-1)

3、人肝微粒體(Corning Gentest，產品目錄號452161，批次號905002) 3. Human liver microsomes (Corning Gentest, catalog number 452161, batch number 905002)

4、Thermo UHPLC-Q-Exactive Orbitrap質譜儀(Thermo Fisher Scientific) 4. Thermo UHPLC-Q-Exactive Orbitrap mass spectrometer (Thermo Fisher Scientific)

5、Acquity BEH C₁₈管柱，2.1×100mm，1.7μm(美國Waters公司) 5. Acquity BEH C ₁₈ column, 2.1×100mm, 1.7μm (Waters, USA)

6、陽性對照化合物(雙氯芬酸，Diclofenac)。 6. Positive control compound (Diclofenac, Diclofenac).

二、實驗藥品 2. Experimental Drugs

實施例2化合物、化合物XL-092(見WO2019148044A1第162頁實施例8化合物)，其結構如下： The compound of Example 2, compound XL-092 (see Example 8 compound on page 162 of WO2019148044A1), has the following structure:

三、實驗步驟 3. Experimental steps

1、受試化合物溶液配製：取受試化合物適量，精密稱定，加入適量的DMSO溶解後混合均勻，即得濃度為30mM的儲備溶液。將濃度為10mM的儲備液用50%乙腈/水(v/v)稀釋10倍，得到濃度為3.0mM的工作溶液1。將濃度為3.0mM的工作溶液1用PBS稀釋10倍，得到300μM的工作溶液2，使用前於4℃保存。 1. Preparation of the test compound solution: take an appropriate amount of the test compound, accurately weigh it, add an appropriate amount of DMSO to dissolve and mix evenly to obtain a stock solution with a concentration of 30 mM. The stock solution with a concentration of 10 mM was diluted 10 times with 50% acetonitrile/water (v/v) to obtain a working solution with a concentration of 3.0 mM. Liquid 1. Working solution 1 with a concentration of 3.0 mM was diluted 10 times with PBS to obtain 300 μM working solution 2, which was stored at 4°C before use.

2、磷酸緩衝液配製：分別稱取K₂HPO₄和KH₂PO₄適量，溶於4L的純水中，配成濃度為100mM的緩衝溶液，然後用磷酸或者氫氧化鈉調整pH值為7.4。 2. Preparation of phosphate buffer solution: Weigh appropriate amount of K ₂ HPO ₄ and KH ₂ PO ₄ respectively, dissolve them in 4L of pure water to make a buffer solution with a concentration of 100mM, and then adjust the pH value to 7.4 with phosphoric acid or sodium hydroxide .

3、肝微粒體溶液配製：分別取各個種屬的肝微粒體儲存液(濃度為20mg/mL)適量，用濃度為100mM的磷酸緩衝液(pH 7.4)稀釋到1.43mg/mL微粒體溶液。 3. Preparation of liver microsome solution: Take an appropriate amount of liver microsome stock solution (concentration: 20 mg/mL) of each species, and dilute to 1.43 mg/mL microsome solution with 100 mM phosphate buffer (pH 7.4).

4、NADPH輔因子溶液的配製：稱取NADPH和氯化鎂適量，溶於適量的濃度為100mM的磷酸緩衝液(pH值為7.4)中，使得NADPH和氯化鎂的濃度分別為10mM和30mM，備用。 4. Preparation of NADPH cofactor solution: Weigh an appropriate amount of NADPH and magnesium chloride, dissolve in an appropriate amount of phosphate buffer (pH 7.4) with a concentration of 100 mM, so that the concentrations of NADPH and magnesium chloride are 10 mM and 30 mM respectively, and set aside.

5、谷胱甘肽(GSH)溶液的配製：稱取GSH適量，溶於適量的濃度為100mM的磷酸緩衝液(pH值為7.4)中，使得GSH的濃度為50mM，備用。 5. Preparation of glutathione (GSH) solution: Take an appropriate amount of GSH, dissolve it in an appropriate amount of 100 mM phosphate buffer (pH 7.4), so that the concentration of GSH is 50 mM, and set aside.

6、孵育體系如下所示： 6. The incubation system is as follows:

精密移取20μL濃度為300μM的工作液2，加入到1.5mL離心管中，再加入140μL濃度為1.43mg/mL的肝微粒體溶液，使得孵育體系中肝微粒體蛋白濃度為1mg/mL。再加入20μL濃度為10mM的NADPH溶液和20μL濃度為50mM的GSH溶液後，放入37℃恆溫孵育箱中震盪孵育，並開始計時。孵育開始60min後，從孵育箱中取出孵育樣品，加入1000μL冰冷乙腈溶液，終止反應並在室溫下放置10min後，12000rpm離心10min。移取全部上清液於離心管中，37℃真空濃縮至乾。殘留物用200μL 25%乙腈/水溶液複溶，12000rpm離心10min，移取上清液至96孔板中，吸取5μL進行LC/MS分析。對於空白樣品，加入20μL PBS代替工作液2。對於NCF樣品，加入20μL PBS代替GSH溶液。陽性對照雙氯芬酸(10μM)同受試化合物。採集數據經Xcalibur軟件處理分析，根據精確分子量，二級質譜碎片分析本揭露化合物是否會發生代謝活化產生反應性代謝產物。 Precisely pipette 20 μL of working solution 2 with a concentration of 300 μM, add it to a 1.5 mL centrifuge tube, and then add 140 μL of liver microsomal solution with a concentration of 1.43 mg/mL, so that the concentration of liver microsomal protein in the incubation system is 1 mg/mL. After adding 20 μL of NADPH solution with a concentration of 10 mM and 20 μL of GSH solution with a concentration of 50 mM, put it into a constant temperature incubator at 37° C. for shaking incubation, and start timing. After 60 minutes of incubation, the incubation samples were taken out from the incubator, and 1000 μL of ice-cold acetonitrile solution was added to terminate the reaction and left at room temperature for 10 minutes, then centrifuged at 12000 rpm for 10 minutes. Pipette all supernatants into centrifuge tubes and concentrate to dryness in vacuo at 37°C. The residue was redissolved in 200 μL of 25% acetonitrile/water solution, centrifuged at 12000 rpm for 10 min, the supernatant was transferred to a 96-well plate, and 5 μL was pipetted for LC/MS analysis. For blank samples, add 20 μL PBS instead of working solution 2. For NCF samples, add 20 µL of PBS instead of GSH solution. The positive control diclofenac (10 μM) was the same as the test compound. The collected data is processed and analyzed by Xcalibur software, and according to the accurate molecular weight, the fragmentation of MS/MS is used to analyze whether the disclosed compound will undergo metabolic activation to produce reactive metabolites.

表2 本揭露化合物在人肝微粒體中反應性代謝產物鑑定

Table 2 Identification of reactive metabolites of the disclosed compounds in human liver microsomes

結論：實驗中未檢測到與本揭露實施例2化合物相關的GSH結合物，但檢測到與化合物XL-092相關的GSH結合物，由此可知，本揭露的化合物較化合物XL-092表現出更好的安全性。 Conclusion: GSH conjugates related to the compound of Example 2 of the present disclosure were not detected in the experiment, but GSH conjugates related to the compound XL-092 were detected. It can be seen that the compound of the present disclosure shows more good security.

Claims

一種通式(I)所示的化合物或其可藥用的鹽， A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof,

其中， in,

G₁為N原子或CR^2a； G ₁ is N atom or CR ^2a ;

G₂為N原子或CR^2b； G ₂ is N atom or CR ^2b ;

G₃為N原子或CR^3a； G ₃ is N atom or CR ^3a ;

n為0、1、2、3、4或5；且 n is 0, 1, 2, 3, 4 or 5; and

m為1、2、3、4、5或6。 m is 1, 2, 3, 4, 5 or 6.

如請求項1所述的通式(I)所示的化合物或其可藥用的鹽，其中G₁為CR^2a；G₂為CR^2b或N原子；G₃為CR^3a；R^2a、R^2b和R^3a相同或不同，且各自獨立地選自氫原子、鹵素和C_1-6烷基；較佳地，G₁為CR^2a；G₂為CR^2b；G₃為CR^3a；R^2a、R^2b和R^3a相同或不同，且各自獨立地選自氫原子、鹵素和C_1-6烷基。 A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof as claimed in item 1, wherein G ₁ is CR ^2a ; G ₂ is CR ^2b or N atom; G ₃ is CR ^3a ; R ^2a , R ^2b and R ^3a are the same or different, and are each independently selected from hydrogen atom, halogen and C _1-6 alkyl; preferably, G ₁ is CR ^2a ; G ₂ is CR ^2b ; G ₃ is CR ^3a ; R ^2a , R ^2b and R ^3a are the same or different, and are each independently selected from a hydrogen atom, a halogen and a C _1-6 alkyl group.

如請求項1或2所述的通式(I)所示的化合物或其可藥用的鹽，其為通式(II)所示的化合物或其可藥用的鹽， The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof as described in Claim 1 or 2, which is the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof,

其中， in,

環A、R¹至R⁵和n如請求項1中所定義。 Ring A, R ¹ to R ⁵ and n are as defined in claim 1.

如請求項1至3中任一項所述的通式(I)所示的化合物或其可藥用的鹽，其中環A為苯基或環己基。 The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 3, wherein ring A is phenyl or cyclohexyl.

如請求項1至4中任一項所述的通式(I)所示的化合物或其可藥用的鹽，其中R⁴為C_1-6烷基；較佳地，R⁴為甲基。 The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 4, wherein R ⁴ is C _1-6 alkyl; preferably, R ⁴ is methyl .

如請求項1至5中任一項所述的通式(I)所示的化合物或其可藥用的鹽，其中R⁵為C_1-6烷基或-(CH₂)_mR^a；R^a為3至6員環烷基，其中該3至6員環烷基視需要被選自C_1-6烷基和-NR^bR^c中的一個或多個取代基所取代；R^b和R^c相同或不同，且各自獨立地為氫原子或C_1-6烷基；m為1、2或3；較佳地，R⁵為甲基或

。 A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 5, wherein R ⁵ is C _1-6 alkyl or -(CH ₂ ) _m R ^a ; R ^a is a 3 to 6 membered cycloalkyl group, wherein the 3 to 6 membered cycloalkyl group is optionally substituted by one or more substituents selected from C _1-6 alkyl and -NR ^b R ^c ; R ^b and R ^c are the same or different, and each independently is a hydrogen atom or a C _1-6 alkyl group; m is 1, 2 or 3; preferably, R ⁵ is methyl or

.

如請求項1至6中任一項所述的通式(I)所示的化合物或其可藥用的鹽，其中各個R¹相同或不同，且各自獨立地選自氫原子、鹵素、C_1-6烷基、C_1-6烷氧基、C_1-6鹵烷基、C_1-6鹵烷氧基、氰基、胺基、硝基、羥基、C_1-6羥烷基、3至6員環烷基和3至6員雜環基；較佳地，各個R¹相同或不同，且各自獨立地選自氫原子、鹵素、C_1-6烷基和C_1-6鹵烷基。 The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 6, wherein each R ¹ is the same or different, and each independently selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, cyano, amino, nitro, hydroxyl, C _1-6 hydroxyalkyl, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocyclic group; preferably, each R ¹ is the same or different, and each independently selected from hydrogen atom, halogen, C _1-6 alkyl and C _1-6 halogen alkyl.

如請求項1至7中任一項所述的通式(I)所示的化合物或其可藥用的鹽，其中R²選自氫原子、鹵素和C_1-6烷基。 The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 7, wherein R ² is selected from hydrogen atom, halogen and C _1-6 alkyl.

如請求項1至8中任一項所述的通式(I)所示的化合物或其可藥用的鹽，其中R³選自氫原子、鹵素和C_1-6烷基。 The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 8, wherein R ³ is selected from hydrogen atom, halogen and C _1-6 alkyl.

如請求項1至9中任一項所述的通式(I)所示的化合物或其可藥用的鹽，其中n為0或1。 A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 9, wherein n is 0 or 1.

如請求項1至10中任一項所述的通式(I)所示的化合物或其可藥用的鹽，其選自以下化合物： A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 10, which is selected from the following compounds:

一種通式(IA)所示的化合物或其鹽， A compound represented by general formula (IA) or a salt thereof,

其中， in,

G₁、G₂、G₃和R²至R⁵如請求項1中所定義。 G ₁ , G ₂ , G ₃ and R ² to R ⁵ are as defined in claim 1.

一種選自如下結構的化合物， A compound selected from the following structures,

一種通式(IC)所示的化合物或其鹽， A compound represented by general formula (IC) or a salt thereof,

其中， in,

Y為鹵素；較佳為溴原子； Y is a halogen; preferably a bromine atom;

如請求項14所述的通式(IC)所示的化合物或其鹽，其選自以下化合物： The compound represented by the general formula (IC) or its salt as claimed in item 14, which is selected from the following compounds:

一種製備如請求項1所述的通式(I)所示的化合物或其可藥用的鹽的方法，該方法包括： A method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1, the method comprising:

其中， in,

X為鹵素；較佳為氯原子； X is a halogen; preferably a chlorine atom;

環A、G₁、G₂、G₃、R¹至R⁵和n如請求項1中所定義。 Ring A, G ₁ , G ₂ , G ₃ , R ¹ to R ⁵ and n are as defined in claim 1.

其中， in,

Y為鹵素；較佳為溴原子； Y is a halogen; preferably a bromine atom;

一種醫藥組成物，該醫藥組成物含有如請求項1至11中任一項所述的通式(I)所示的化合物或其可藥用的鹽，以及一種或多種藥學上可接受的載體、稀釋劑或賦形劑。 A pharmaceutical composition, which contains a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof as described in any one of claim items 1 to 11, and one or more pharmaceutically acceptable carriers , diluent or excipient.

一種如請求項1至11中任一項所述的通式(I)所示的化合物或其可藥用的鹽或如請求項18所述的醫藥組成物在製備用於抑制蛋白激酶的藥物中的用途；較佳地，其中該蛋白激酶為受體酪胺酸激酶(RTKs)。 A compound represented by general formula (I) as described in any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described in claim 18 in the preparation of a drug for inhibiting protein kinase Use in; preferably, wherein the protein kinases are receptor tyrosine kinases (RTKs).

如請求項19所述的用途，其中該受體酪胺酸激酶(RTKs)為Axl、Mer、TYRO3、MET、KDR或它們的組合。 The use as claimed in claim 19, wherein the receptor tyrosine kinases (RTKs) are Axl, Mer, TYRO3, MET, KDR or a combination thereof.

一種如請求項1至11中任一項所述的通式(I)所示的化合物或其可藥用的鹽或如請求項18所述的醫藥組成物在製備用於治療和/或預防疾病、病症和綜合症的藥物中的用途；其中該疾病、病症和綜合症選自肉瘤、多發性骨髓瘤、白血病、黏液瘤、橫紋肌瘤、平滑肌瘤、纖維瘤、脂肪瘤、畸胎瘤、咽喉癌、口腔癌、肺癌、肺泡癌、淋巴瘤、間皮瘤、結直腸癌、小腸癌、胃癌、食道癌、胰腺癌、乳腺癌、子宮內膜癌、卵巢癌、輸卵管癌、宮頸癌、腎癌、膀胱癌、***癌、睾丸癌、肝癌、膽管癌、神經膠質瘤、神經母細胞瘤、黑色素瘤、皮膚癌、基底細胞癌、鱗狀細胞癌、甲狀腺癌、頭頸癌、唾液腺癌、銀屑病、胃腸道間質瘤、動脈粥樣硬化和肺纖維化；其中該咽喉癌較佳為鼻咽癌；該肉瘤較佳為骨肉瘤或軟骨肉瘤；該結直腸癌較佳為結腸癌或直腸癌；該纖維瘤較佳為神經纖維瘤。 A compound represented by general formula (I) as described in any one of claim items 1 to 11 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described in claim item 18 is used for treatment and/or prevention Use in medicine for diseases, disorders and syndromes; wherein the diseases, disorders and syndromes are selected from the group consisting of sarcoma, multiple myeloma, leukemia, myxoma, rhabdomyoma, leiomyoma, fibroma, lipoma, teratoma , throat cancer, oral cancer, lung cancer, alveolar cancer, lymphoma, mesothelioma, colorectal cancer, small intestine cancer, stomach cancer, esophageal cancer, pancreatic cancer, breast cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, cervical cancer , kidney cancer, bladder cancer, prostate cancer, testicular cancer, liver cancer, cholangiocarcinoma, glioma, neuroblastoma, melanoma, skin cancer, basal cell carcinoma, squamous cell carcinoma, thyroid cancer, head and neck cancer, salivary gland cancer , psoriasis, gastrointestinal stromal tumor, atherosclerosis and pulmonary fibrosis; wherein the throat cancer is preferably nasopharyngeal carcinoma; the sarcoma is preferably osteosarcoma or chondrosarcoma; the colorectal cancer is preferably colon Carcinoma or rectal cancer; the fibroma is preferably a neurofibroma.

一種如請求項1至11中任一項所述的通式(I)所示的化合物或其可藥用的鹽或如請求項18所述的醫藥組成物在製備用於治療和或預防腫瘤的藥物中的用途；其中該腫瘤選自肉瘤、多發性骨髓瘤、白血病、黏液瘤、橫紋肌瘤、平滑肌瘤、纖維瘤、脂肪瘤、畸胎瘤、咽喉癌、口腔癌、肺癌、肺泡癌、淋巴瘤、間皮瘤、結直腸癌、小腸癌、胃癌、食道癌、胰腺癌、乳腺癌、子宮內膜癌、卵巢癌、輸卵管癌、宮頸癌、腎癌、膀胱癌、***癌、睾丸癌、肝癌、膽管癌、神經膠質瘤、神經母細胞瘤、黑色素瘤、皮膚癌、基底細胞癌、鱗狀細胞癌、甲狀腺癌、頭頸癌、唾液腺癌和胃腸道間質瘤；其中該咽喉癌較佳為鼻咽癌；該肉瘤較佳為骨肉瘤或軟骨肉瘤；該結直腸癌較佳為結腸癌或直腸癌；該纖維瘤較佳為神經纖維瘤。 A compound represented by general formula (I) as described in any one of claim items 1 to 11 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described in claim item 18 is used for treating and or preventing tumors wherein the tumor is selected from the group consisting of sarcoma, multiple myeloma, leukemia, myxoma, rhabdomyoma, leiomyoma, fibroma, lipoma, teratoma, throat cancer, oral cavity cancer, lung cancer, alveolar cancer , lymphoma, mesothelioma, colorectal cancer, small intestine cancer, stomach cancer, esophagus cancer, pancreatic cancer, breast cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, cervical cancer, kidney cancer, bladder cancer Carcinoma, prostate cancer, testicular cancer, liver cancer, cholangiocarcinoma, glioma, neuroblastoma, melanoma, skin cancer, basal cell carcinoma, squamous cell carcinoma, thyroid cancer, head and neck cancer, salivary gland cancer, and gastrointestinal stromal cancer Wherein the throat cancer is preferably nasopharyngeal carcinoma; the sarcoma is preferably osteosarcoma or chondrosarcoma; the colorectal cancer is preferably colon cancer or rectal cancer; the fibroma is preferably neurofibroma.